Compounds

ABSTRACT

There is provided a compound of formula (I): 
                         
or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula 1, and the use of a compound of Formula 1 as a medicament and in the treatment of cancer.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.application Ser. No. 14/751,381 filed Jun. 26, 2015, which claims thebenefit of U.S. application Ser. No. 14/078,918 filed Nov. 13, 2013,which claims the benefit of U.S. application Ser. No. 13/359,008 filedon Jan. 26, 2012 (now U.S. Pat. No. 8,604,022 issued Dec. 10, 2013),which claims the benefit of U.S. application Ser. No. 12/771,661 filedApr. 30, 2010 (now U.S. Pat. No. 8,129,391 issued Mar. 6, 2012), whichclaims the benefit of Ser. No. 11/958,720 filed Dec. 18, 2007 (now U.S.Pat. No. 7,737,149 issued Jun. 15, 2010), which claims the benefit ofU.S. Application No. 60/985,542 filed Nov. 5, 2007 and U.S. ApplicationNo. 60/871,190 filed Dec. 21, 2006.

The present invention relates to pyrazole derivatives, a process fortheir preparation, pharmaceutical compositions containing them, aprocess for preparing the pharmaceutical compositions, and their use intherapy.

Protein kinases are a class of proteins (enzymes) that regulate avariety of cellular functions. This is accomplished by thephosphorylation of specific amino acids on protein substrates resultingin conformational alteration of the substrate protein. Theconformational change modulates the activity of the substrate or itsability to interact with other binding partners. The enzyme activity ofthe protein kinase refers to the rate at which the kinase adds phosphategroups to a substrate. It can be measured, for example, by determiningthe amount of a substrate that is converted to a product as a functionof time. Phosphorylation of a substrate occurs at the active-site of aprotein kinase.

Tyrosine kinases are a subset of protein kinases that catalyze thetransfer of the terminal phosphate of adenosine triphosphate (ATP) totyrosine residues on protein substrates. These kinases play an importantpart in the propagation of growth factor signal transduction that leadsto cellular proliferation, differentiation and migration.

Fibroblast growth factor (FGF) has been recognized as an importantmediator of many physiological processes, such as morphogenesis duringdevelopment and angiogenesis. There are currently over 25 known membersof the FGF family. The fibroblast growth factor receptor (FGFR) familyconsists of four members with each composed of an extracellular ligandbinding domain, a single transmembrane domain and an intracellularcytoplasmic protein tyrosine kinase domain. Upon stimulation with FGF,FGFRs undergo dimerisation and transphosphorylation, which results inreceptor activation. Receptor activation is sufficient for therecruitment and activation of specific downstream signalling partnersthat participate in the regulation of diverse process such as cellgrowth, cell metabolism and cell survival (Reviewed in Eswarakumar, V.P. et. al., Cytokine & Growth Factor Reviews 2005, 16, p 139-149).Consequently, FGF and FGFRs have the potential to initiate and/orpromote tumorigenesis.

There is now considerable evidence directly linking FGF signalling tohuman cancer. The elevated expression of various FGFs has been reportedin a diverse range of tumour types such as bladder, renal cell andprostate (amongst others). FGF has also been described as a powerfulangiogenic factor. The expression of FGFRs in endothelial cells has alsobeen reported. Activating mutations of various FGFRs have beenassociated with bladder cancer and multiple myeloma (amongst others)whilst receptor expression has also been documented in prostate andbladder cancer amongst others (Reviewed in Grose, R. et. al., Cytokine &Growth Factor Reviews 2005, 16, p 179-186 and Kwabi-Addo, B. et. al.,Endocrine-Related Cancer 2004, 11, p 709-724). For these reasons, theFGF signalling system is an attractive therapeutic target, particularlysince therapies targeting FGFRs and/or FGF signalling may affect boththe tumour cells directly and tumour angiogenesis.

In accordance with the present invention, there is provided a compoundof formula (I):

or a pharmaceutically acceptable salt thereofwherein

ring A represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

ring B represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

-   -   R¹ each independently represents        -   a halogen,        -   a hydroxyl group,        -   a cyano group,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₃₋₅cycloalkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶R⁷ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₃alkenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁸R⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a phenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR¹⁰R¹¹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a 4- to 6-membered heterocyclyl group optionally substituted            by one or more substituents selected from C₁-C₃alkyl,            C₁-C₃alkoxy, C₃-cycloalkyl, C₁-C₃alkylthio, —NR¹²R¹³ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a —NR¹⁶R¹⁷ group,        -   a —OCOR¹⁸ group,        -   a —CO₂R¹⁹ group,        -   a —CONR²⁰R²¹ group,        -   a —NR²²COR²³ group,        -   a —NR²⁴CO₂R²⁵ group.        -   a —OSO₂R²⁶ group,        -   or two adjacent R¹ groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR²⁷R²⁸ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R² each independently represents        -   a hydroxyl group,        -   a halogen,        -   a cyano group,        -   a —CO₂R²⁹ group,        -   a —CONR³⁰R³¹ group,        -   a —NR³²COR³³ group,        -   a —NR³⁴CO₂R³⁵ group,        -   a —NR³⁶R³⁷ group,        -   a —SO₂R³⁸ group,        -   a —SO₂NR³⁹R⁴⁰ group,        -   a —NR⁴¹SO₂R⁴² group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴³R⁴⁴ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl trifluoromethyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- and            di-C₁-C₃alkylamino, cyano, hydroxyl, trifluoromethyl),            halogen, hydroxyl, and a 4- to 7-membered heterocyclyl group            optionally fused a 4- to 7-membered carbocyclyl or            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), cyano, halogen and hydroxyl,        -   a C₃-C₆cycloalkyl group optionally substituted by one or            more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁸R⁴⁹ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl, and a 4-            to 7-membered heterocyclyl group optionally substituted by            one or more substituents selected from C₁-C₆alkyl,            C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁰R⁵¹ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₆alkenyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵²R⁵³ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, hydroxyl, and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁴R⁵⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a 4- to 7-membered heterocyclyl group optionally fused to a            4- to 7-membered carbocyclyl or heterocyclyl group and            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,            C₁-C₆alkylcarbonyl, C₃-C₆cycloalkyl, C₁-C₆alkylthio,            —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may be optionally            substituted by one or more substituents selected from            halogen, cyano, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, oxo, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₆alkoxy group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            —NR⁶²R⁶³ (each of which may be optionally substituted by one            or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   or two adjacent R² groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶⁶R⁶⁷ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁶⁸R⁶⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl;    -   a is 0, 1, 2, 3 or 4;    -   b is 0, 1, 2, 3 or 4;    -   R⁴ and R⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴ and R⁵ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶ and R⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶ and R⁷ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁸ and R⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁰ and R¹¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁰ and R¹¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹² and R¹³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹² and R¹³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁴ and R¹⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁴ and R¹⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁶ and R¹⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁶ and R¹⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R¹⁸ represents C₁-C₄alkyl, or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R¹⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²⁰ and R²¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁰ and R²¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²³ represents C₁-C₄alkyl or C₃-C₆cycloalkyl(each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁵ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁶ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁷ and R²⁸ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁷ and R²⁸ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R²⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁰ and R³¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁰ and R³¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³² represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³³ represents hydrogen, C₁-C₄alkyl, C₃-C₆cycloalkyl or a 5- or        6-membered aromatic group optionally comprising at least one        ring heteroatom selected from nitrogen, oxygen and sulphur (each        of which may be optionally substituted by one or more        substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,        C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,        hydroxyl and trifluoromethyl);    -   R³⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁵ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁶ and R³⁷ each independently represent hydrogen, C₁-C₄alkyl,        C₂-C₄alkynyl, C₃-C₆cycloalkyl or a 5- or 6-membered aromatic        group optionally comprising at least one ring heteroatom        selected from nitrogen, oxygen and sulphur, or R³⁶ and R³⁷        together with the nitrogen atom to which they are attached form        a 4- to 6-membered saturated heterocycle (each of which may be        optionally substituted by one or more substituents selected from        halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),        mono- and di-C₁-C₃alkylamino, hydroxyl, trifluoromethyl and 4-        to 7-membered carbocyclyl or heterocycly group which may be        optionally substituted by one or more substituents selected from        halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),        mono- and di-C₁-C₃alkylamino, hydroxyl, trifluoromethyl);    -   R³⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁹ and R⁴⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁹ and R⁴⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R⁴¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴³ and R⁴⁴ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴³ and R⁴⁴ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁵ and R⁴⁶ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁵ and R⁴⁶ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁷ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁴⁸ and R⁴⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁸ and R⁴⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁰ and R⁵¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁰ and R⁵¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵² and R⁵³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵² and R⁵³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁴ and R⁵⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁴ and R⁵⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁶ and R⁵⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁶ and R⁵⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁵⁹ and R⁶⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁹ and R⁶⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶¹ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁶² and R⁶³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶² and R⁶³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁴ and R⁶⁵ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁴ and R⁶⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁶ and R⁶⁷ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁶ and R⁶⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁸ and R⁶⁹ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁸ and R⁶⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle; and where    -   when Y represents CH₂, X represents CH₂, O, NR⁷⁰ or S(O)x        wherein R⁷⁰ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and x is 0, 1 or 2; or    -   when X represents CH₂, Y represents CH₂, O, NR⁷¹ or S(O)_(y)        wherein R⁷¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and y is 0, 1 or 2.

In accordance with the present invention, there is provided a compoundof formula (I):

or a pharmaceutically acceptable salt thereofwherein

ring A represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

ring B represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

-   -   R¹ each independently represents        -   a halogen,        -   a hydroxyl group,        -   a cyano group,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₃₋₅-cycloalkyl group optionally substituted by one or            more substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶R⁷ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₃alkenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁸R⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a phenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR¹⁰R¹¹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a 4- to 6-membered heterocyclyl group optionally substituted            by one or more substituents selected from C₁-C₃alkyl,            C₁-C₃alkoxy, C₃-cycloalkyl, C₁-C₃alkylthio, —NR¹²R¹³ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a —NR¹⁶R¹⁷ group,        -   a —OCOR¹⁸ group,        -   a —CO₂R¹⁹ group,        -   a —CONR²⁰R²¹ group,        -   a —NR²²COR²³ group,        -   a —NR²⁴CO₂R²⁵ group.        -   a —OSO₂R²⁶ group,        -   or two adjacent R¹ groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR²⁷R²⁸ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R² each independently represents        -   a hydroxyl group,        -   a halogen,        -   a cyano group,        -   a —CO₂R²⁹ group,        -   a —CONR³⁰R³¹ group,        -   a —NR³²COR³³ group,        -   a —NR³⁴CO₂R³⁵ group,        -   a —NR³⁶R³⁷ group,        -   a —SO₂R³⁸ group,        -   a —SO₂NR³⁹R⁴⁰ group,        -   a —NR⁴¹SO₂R⁴² group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴³R⁴⁴ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl trifluoromethyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- and            di-C₁-C₃alkylamino, cyano, hydroxyl, trifluoromethyl),            halogen, hydroxyl, and a 4- to 7-membered heterocyclyl group            optionally fused to a 4- to 7-membered carbocyclyl or            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), cyano, halogen and hydroxyl,        -   a C₃-C₆cycloalkyl group optionally substituted by one or            more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁸R⁴⁹ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl, and a 4-            to 7-membered heterocyclyl group optionally substituted by            one or more substituents selected from C₁-C₆alkyl,            C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁰R⁵¹ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₆alkenyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵²R⁵³, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, hydroxyl, and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁴R⁵⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a 4- to 7-membered heterocyclyl group optionally fused to a            4- to 7-membered carbocyclyl or heterocyclyl group and            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,            C₁-C₆alkylcarbonyl, C₃-C₆cycloalkyl, C₁-C₆alkylthio,            —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may be optionally            substituted by one or more substituents selected from            halogen, cyano, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, oxo, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₆alkoxy group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            —NR⁶²R⁶³ (each of which may be optionally substituted by one            or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   or two adjacent R² groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶⁶R⁶⁷ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁶⁸R⁶⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl;    -   a is 0, 1, 2, 3 or 4;    -   b is 0, 1, 2, 3 or 4;    -   R⁴ and R⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴ and R⁵ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶ and R⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶ and R⁷ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁸ and R⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁰ and R¹¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁰ and R¹¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹² and R¹³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹² and R¹³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁴ and R¹⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁴ and R¹⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁶ and R¹⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁶ and R¹⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R¹⁸ represents C₁-C₄alkyl, or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R¹⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²⁰ and R²¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁰ and R²¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²³ represents C₁-C₄alkyl or C₃-C₆cycloalkyl(each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁵ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁶ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁷ and R²⁸ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁷ and R²⁸ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R²⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁰ and R³¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁰ and R³¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³² represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³³ represents hydrogen, C₁-C₄alkyl, C₃-C₆cycloalkyl or a 5- or        6-membered aromatic group optionally comprising at least one        ring heteroatom selected from nitrogen, oxygen and sulphur (each        of which may be optionally substituted by one or more        substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,        C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,        hydroxyl and trifluoromethyl);    -   R³⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁵ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁶ and R³⁷ each independently represent hydrogen, C₁-C₄alkyl,        C₂-C₄alkynyl, C₃-C₆cycloalkyl or a 5- or 6-membered aromatic        group optionally comprising at least one ring heteroatom        selected from nitrogen, oxygen and sulphur, or R³⁶ and R³⁷        together with the nitrogen atom to which they are attached form        a 4- to 6-membered saturated heterocycle (each of which may be        optionally substituted by one or more substituents selected from        halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),        mono- and di-C₁-C₃alkylamino, hydroxyl, trifluoromethyl and 4-        to 7-membered carbocyclyl or heterocycly group which may be        optionally substituted by one or more substituents selected from        halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),        mono- and di-C₁-C₃alkylamino, hydroxyl, trifluoromethyl);    -   R³⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁹ and R⁴⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁹ and R⁴⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R⁴¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴³ and R⁴⁴ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴³ and R⁴⁴ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁵ and R⁴⁶ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁵ and R⁴⁶ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁷ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁴⁸ and R⁴⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁸ and R⁴⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁰ and R⁵¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁰ and R⁵¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵² and R⁵³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵² and R⁵³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁴ and R⁵⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁴ and R⁵⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁶ and R⁵⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁶ and R⁵⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁵⁹ and R⁶⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁹ and R⁶⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶¹ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁶² and R⁶³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶² and R⁶³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁴ and R⁶⁵ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁴ and R⁶⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁶ and R⁶⁷ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁶ and R⁶⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁸ and R⁶⁹ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁸ and R⁶⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle; and where    -   when Y represents CH₂, X represents CH₂, O, NR⁷⁰ or S(O)x        wherein R⁷⁰ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and x is 0, 1 or 2; or    -   when X represents CH₂, Y represents CH₂, O, NR⁷¹ or S(O)_(y)        wherein R⁷¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and y is 0, 1 or 2; and        provided that the compound is not

-   4-benzamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,

-   6-anilino-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,

-   prop-2-enyl    N-[5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridin-2-yl]carbamate,

-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-pyrazol-1-yl-pyridine-3-carboxamide,

-   or methyl    6-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-3-carboxylate.

In accordance with a further aspect of the present invention, there isprovided a compound of formula (I):

or a pharmaceutically acceptable salt thereofwherein

ring A represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

ring B represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

-   -   R¹ each independently represents        -   a halogen,        -   a hydroxyl group,        -   a cyano group,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₃₋₅-cycloalkyl group optionally substituted by one or            more substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶R⁷ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₃alkenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁸R⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a phenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR^(1I)R¹¹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a 4- to 6-membered heterocyclyl group optionally substituted            by one or more substituents selected from C₁-C₃alkyl,            C₁-C₃alkoxy, C₃-cycloalkyl, C₁-C₃alkylthio, —NR¹²R¹³ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a —NR¹⁶R¹⁷ group,        -   a —OCOR¹⁸ group,        -   a —CO₂R¹⁹ group,        -   a —CONR²⁰R²¹ group,        -   a —NR²²COR²³ group,        -   a —NR²⁴CO₂R²⁵ group.        -   a —OSO₂R²⁶ group,        -   or two adjacent R¹ groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR²⁷R²⁸ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R² each independently represents        -   a hydroxyl group,        -   a halogen,        -   a cyano group,        -   a —CO₂R²⁹ group,        -   a —CONR³⁰R³¹ group,        -   a —NR³²COR³³ group,        -   a —NR³⁴CO₂R³⁵ group,        -   a —NR³⁶R³⁷ group,        -   a —SO₂R³⁸ group,        -   a —SO₂NR³⁹R⁴⁰ group,        -   a —NR⁴¹SO₂R⁴² group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴³R⁴⁴ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl trifluoromethyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- and            di-C₁-C₃alkylamino, cyano, hydroxyl, trifluoromethyl),            halogen, hydroxyl, and a 4- to 7-membered heterocyclyl group            optionally fused to a 4- to 7-membered carbocyclyl or            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), cyano, halogen and hydroxyl,        -   a C₃-C₆cycloalkyl group optionally substituted by one or            more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁸R⁴⁹ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl, and a 4-            to 7-membered heterocyclyl group optionally substituted by            one or more substituents selected from C₁-C₆alkyl,            C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁰R⁵¹ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₆alkenyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵²R⁵³, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, hydroxyl, and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁴R⁵⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a 4- to 7-membered heterocyclyl group optionally fused to a            4- to 7-membered carbocyclyl or heterocyclyl group and            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylcarbonyl,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷ SO₂R⁵⁸ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₆alkoxy group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            —NR⁶²R⁶³ (each of which may be optionally substituted by one            or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   or two adjacent R² groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶⁶R⁶⁷ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁶⁸R⁶⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl;    -   a is 0, 1, 2, 3 or 4;    -   b is 0, 1, 2, 3 or 4;    -   R⁴ and R⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴ and R⁵ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶ and R⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶ and R⁷ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁸ and R⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁰ and R¹¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁰ and R¹¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹² and R¹³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹² and R¹³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁴ and R¹⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁴ and R¹⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁶ and R¹⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁶ and R¹⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R¹⁸ represents C₁-C₄alkyl, or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R¹⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²⁰ and R²¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁰ and R²¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²³ represents C₁-C₄alkyl or C₃-C₆cycloalkyl(each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁵ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁶ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁷ and R²⁸ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁷ and R²⁸ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R²⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁰ and R³¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁰ and R³¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³² represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³³ represents hydrogen, C₁-C₄alkyl, C₃-C₆cycloalkyl or a 5- or        6-membered aromatic group optionally comprising at least one        ring heteroatom selected from nitrogen, oxygen and sulphur (each        of which may be optionally substituted by one or more        substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,        C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,        hydroxyl and trifluoromethyl);    -   R³⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁵ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁶ and R³⁷ each independently represent hydrogen, C₁-C₄alkyl,        C₂-C₄alkynyl, C₃-C₆cycloalkyl or a 5- or 6-membered aromatic        group optionally comprising at least one ring heteroatom        selected from nitrogen, oxygen and sulphur, or R³⁶ and R³⁷        together with the nitrogen atom to which they are attached form        a 4- to 6-membered saturated heterocycle (each of which may be        optionally substituted by one or more substituents selected from        halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),        mono- and di-C₁-C₃alkylamino, hydroxyl, trifluoromethyl and 4-        to 7-membered carbocyclyl or heterocycly group which may be        optionally substituted by one or more substituents selected from        halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),        mono- and di-C₁-C₃alkylamino, hydroxyl, trifluoromethyl);    -   R³⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁹ and R⁴⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁹ and R⁴⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R⁴¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴³ and R⁴⁴ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴³ and R⁴⁴ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁵ and R⁴⁶ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁵ and R⁴⁶ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁷ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁴⁸ and R⁴⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁸ and R⁴⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁰ and R⁵¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁰ and R⁵¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵² and R⁵³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵² and R⁵³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁴ and R⁵⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁴ and R⁵⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁶ and R⁵⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁶ and R⁵⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁵⁹ and R⁶⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁹ and R⁶⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶¹ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁶² and R⁶³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶² and R⁶³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁴ and R⁶⁵ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁴ and R⁶⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁶ and R⁶⁷ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁶ and R⁶⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁸ and R⁶⁹ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁸ and R⁶⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle; and where    -   when Y represents CH₂, X represents CH₂, O, NR⁷⁰ or S(O)x        wherein R⁷⁰ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and x is 0, 1 or 2; or    -   when X represents CH₂, Y represents CH₂, O, NR⁷¹ or S(O)_(y)        wherein R⁷¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and y is 0, 1 or 2.

In accordance with a further aspect of the present invention, there isprovided a compound of formula (I):

or a pharmaceutically acceptable salt thereofwherein

ring A represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

ring B represents a 5- or 6-membered aromatic group optionallycomprising at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

-   -   R¹ each independently represents        -   a halogen,        -   a hydroxyl group,        -   a cyano group,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₃₋₅-cycloalkyl group optionally substituted by one or            more substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶R⁷ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₃alkenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁸R⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a phenyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR^(1I)R¹¹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a 4- to 6-membered heterocyclyl group optionally substituted            by one or more substituents selected from C₁-C₃alkyl,            C₁-C₃alkoxy, C₃-cycloalkyl, C₁-C₃alkylthio, —NR¹²R¹³ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a —NR¹⁶R¹⁷ group,        -   a —OCOR¹⁸ group,        -   a —CO₂R¹⁹ group,        -   a —CONR²⁰R²¹ group,        -   a —NR²²COR²³ group,        -   a —NR²⁴CO₂R²⁵ group.        -   a —OSO₂R²⁶ group,        -   or two adjacent R¹ groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR²⁷R²⁸ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R² each independently represents        -   a hydroxyl group,        -   a halogen,        -   a cyano group,        -   a —CO₂R²⁹ group,        -   a —CONR³⁰R³¹ group,        -   a —NR³²COR³³ group,        -   a —NR³⁴CO₂R³⁵ group,        -   a —NR³⁶R³⁷ group,        -   a —SO₂R³⁸ group,        -   a —SO₂NR³⁹R⁴⁰ group,        -   a —NR⁴¹SO₂R⁴² group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴³R⁴⁴ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl trifluoromethyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- and            di-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl),            halogen, hydroxyl, and a 4- to 7-membered heterocyclyl group            optionally fused to a 4- to 7-membered carbocyclyl or            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₃-C₆cycloalkyl group optionally substituted by one or            more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁸R⁴⁹ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl, and a 4-            to 7-membered heterocyclyl group optionally substituted by            one or more substituents selected from C₁-C₆alkyl,            C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁰R⁵¹ (each            of which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₂-C₆alkenyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵²R⁵³, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, hydroxyl, and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁴R⁵⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a 4- to 7-membered heterocyclyl group optionally fused to a            4- to 7-membered carbocyclyl or heterocyclyl group and            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, hydroxyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₆alkoxy group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            —NR⁶²R⁶³ (each of which may be optionally substituted by one            or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   or two adjacent R² groups together with the atoms to which            they are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁶⁶R⁶⁷ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁶⁸R⁶⁹ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl;    -   a is 0, 1, 2, 3 or 4;    -   b is 0, 1, 2, 3 or 4;    -   R⁴ and R⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴ and R⁵ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶ and R⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶ and R⁷ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁸ and R⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to        which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁰ and R¹¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁰ and R¹¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹² and R¹³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹² and R¹³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁴ and R¹⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁴ and R¹⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R¹⁶ and R¹⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R¹⁶ and R¹⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R¹⁸ represents C₁-C₄alkyl, or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R¹⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²⁰ and R²¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁰ and R²¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R²² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²³ represents C₁-C₄alkyl or C₃-C₆cycloalkyl(each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁵ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁶ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R²⁷ and R²⁸ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R²⁷ and R²⁸ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R²⁹ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁰ and R³¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁰ and R³¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³² represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³³ represents hydrogen, C₁-C₄alkyl, C₃-C₆cycloalkyl or a 5- or        6-membered aromatic group optionally comprising at least one        ring heteroatom selected from nitrogen, oxygen and sulphur (each        of which may be optionally substituted by one or more        substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,        C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,        hydroxyl and trifluoromethyl);    -   R³⁴ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁵ represents hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl or        C₃-C₆cycloalkyl (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R³⁶ and R³⁷ each independently represent hydrogen, C₁-C₄alkyl,        C₂-C₄alkynyl, C₃-C₆cycloalkyl or a 5- or 6-membered aromatic        group optionally comprising at least one ring heteroatom        selected from nitrogen, oxygen and sulphur, or R³⁶ and R³⁷        together with the nitrogen atom to which they are attached form        a 4- to 6-membered saturated heterocycle (each of which may be        optionally substituted by one or more substituents selected from        halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),        mono- and di-C₁-C₃alkylamino, hydroxyl, trifluoromethyl and 5-        or 6-membered aryl group optionally comprising at least one ring        heteroatom selected from nitrogen, oxygen and sulphur);    -   R³⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl (each of which may        be optionally substituted by one or more substituents selected        from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino        (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R³⁹ and R⁴⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R³⁹ and R⁴⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle (each of which may be optionally substituted by one        or more substituents selected from halogen, C₁-C₃alkyl,        C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- and        di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl);    -   R⁴¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴² represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl (each of        which may be optionally substituted by one or more substituents        selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,        amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and        trifluoromethyl);    -   R⁴³ and R⁴⁴ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴³ and R⁴⁴ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁵ and R⁴⁶ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁵ and R⁴⁶ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁴⁷ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁴⁸ and R⁴⁹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁴⁸ and R⁴⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁰ and R⁵¹ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁰ and R⁵¹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵² and R⁵³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵² and R⁵³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁴ and R⁵⁵ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁴ and R⁵⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁶ and R⁵⁷ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁶ and R⁵⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁵⁸ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁵⁹ and R⁶⁰ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁵⁹ and R⁶⁰ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶¹ represents C₁-C₄alkyl or C₃-C₆cycloalkyl;    -   R⁶² and R⁶³ each independently represent hydrogen, C₁-C₄alkyl or        C₃-C₆cycloalkyl, or R⁶² and R⁶³ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁴ and R⁶⁵ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁴ and R⁶⁵ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁶ and R⁶⁷ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁶ and R⁶⁷ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle;    -   R⁶⁸ and R⁶⁹ each independently represent hydrogen, C₁-C₆alkyl or        C₃-C₆cycloalkyl, or R⁶⁸ and R⁶⁹ together with the nitrogen atom        to which they are attached form a 4- to 6-membered saturated        heterocycle; and where    -   when Y represents CH₂, X represents CH₂, O, NR⁷⁰ or S(O)x        wherein R⁷⁰ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and x is 0, 1 or 2; or    -   when X represents CH₂, Y represents CH₂, O, NR⁷¹ or S(O)_(y)        wherein R⁷¹ represents hydrogen, C₁-C₄alkyl or C₃-C₆cycloalkyl        and y is 0, 1 or 2.

In the context of the present specification, unless otherwise indicated,the term “alkyl” includes both linear and branched chain alkyl groups,but references to individual groups such as “n-propyl” are specific forthe linear version only, and references to individual branch chainedversions, for example “i-propyl”, are specific for the branched versiononly. A similar convention applies to other radicals.

For example, examples of “C₁-C₆alkyl” and “C₁-C₄alkyl” include methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. Examples of“C₁-C₆alkoxy” and “C₁-C₃alkoxy” include methoxy, ethoxy, n-propoxy andi-propoxy. Examples of “C₂-C₆alkenyl” include vinyl, allyl and1-propenyl. Examples of “C₃-C₆cycloalkyl” include cyclopropyl,cyclopentyl and cyclohexyl. Example of “mono- and di-C₁-C₆alkylamino”include methylamino, dimethylamino, ethylamino, diethylamino andethylmethylamino. Examples of “C₁-C₆alkylthio” include methylthio,ethylthio and propylthio.

Examples of halogen include fluorine, chlorine, bromine and iodine.

A “4- to 7-membered carbocyclyl group”, unless otherwise stated,includes saturated and fully or partially unsaturated, monocyclic ringscontaining 4, 5, 6 or 7 carbon atoms. A “4- to 7-membered carbocyclylgroup” includes groups such as C₄-C₇cycloalkyl, C₄-C₇cycloalkenyl andC₆aryl.

A “5- or 6-membered aromatic group optionally comprising at least onering heteroatom selected from nitrogen, oxygen and sulphur” or “5- or6-membered aryl group optionally comprising at least one ring heteroatomselected from nitrogen, oxygen and sulphur” is a fully unsaturated,aromatic monocyclic ring containing 5 or 6 atoms of which at least oneis a heteroatom selected from nitrogen, oxygen and sulphur, which may,unless otherwise specified, be carbon or nitrogen linked. Suitably a “5-or 6-membered aromatic ring optionally comprising at least one ringheteroatom selected from nitrogen, oxygen and sulphur” is furyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phenyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, trazinyl and triazolylrings.

A “4- to 7-membered heterocyclyl group”, unless otherwise stated,includes saturated and fully or partially unsaturated, monocyclic ringscontaining 4, 5, 6 or 7 atoms of which at least one is a heteroatomselected from nitrogen, oxygen and sulphur, and which may, unlessotherwise specified, be carbon or nitrogen linked. Suitable “4- to7-membered heterocyclyl group” which may comprise at least one ringheteroatom selected from nitrogen, oxygen and sulphur include azetidine,gamma-butyrolactone, diazepine, dioxolane, dioxane, dihydro-oxazine,dihydrothiophene, dithiolan, furan, hexahydroazepine, imidazole,imidazoline, imidazolidine, isothiazole, isoxazole, morpholine,oxadiazole, oxazine, oxazole, oxetane, piperidine, piperazine,alpha-pyran, gamma-pyran, pyrazine, pyrazolidine, pyrazole, pyrazoline,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline,tetrahydrofuran, tetrahydrofuranone, tetrahydropyran, tetrazine,tetrazole, thiadiazole, thiazole, thiolan, thiomorpholine,thiomorpholine S,S-dioxide, thiophene and triazine.

When R⁴ and R⁵, or R⁶ and R⁷, or R⁸ and R⁹, or R¹⁰ and R¹¹, or R¹² andR¹³, or R¹⁴ and R¹⁵, or R²⁷ and R²⁸, or R⁴³ and R⁴⁴, or R⁴⁵ and R⁴⁶, orR⁴⁸ and R⁴⁹, or R⁵⁰ and R⁵¹, or R⁵² and R⁵³, or R⁵⁴ and R⁵⁵, or R⁵⁶ andR⁵⁷, or R⁵⁹ and R⁶⁰, or R⁶² and R⁶³, or R⁶⁴ and R⁶⁵, or R⁶⁶ and R⁶⁷, orR⁶⁸ and R⁶⁹ represent a 4- to 6-membered saturated heterocycle, itshould be understood that when only one heteroatom is present it is thenitrogen atom to which R⁴ and R⁵, or R⁶ and R⁷, or R⁸ and R⁹, or R¹⁰ andR¹¹, or R¹² and R¹³, or R¹⁴ and R¹⁵, or R²⁷ and R²⁸ or R⁴³ and R⁴⁴, orR⁴⁵ and R⁴⁶, or R⁴⁸ and R⁴⁹, or R⁵⁰ and R⁵¹, or R⁵² and R⁵³, or R⁵⁴ andR⁵⁵, or R⁵⁶ and R⁵⁷, or R⁵⁹ and R⁶⁰, or R⁶² and R⁶³, or R⁶⁴ and R⁶⁵, orR⁶⁶ and R⁶⁷, or R⁶⁸ and R⁶⁹ are attached. The “4- to 6-memberedsaturated heterocycle”, unless otherwise stated, includes saturatedmonocyclic rings containing 4, 5 or 6 atoms wherein at least one atom isnitrogen and the remaining atoms are selected from carbon, nitrogen,oxygen and sulphur. Suitable “4- to 6-membered saturated heterocycle”include pyrrolidine, pyrazolidine, imidazolidine, piperidine,piperazine, morpholine, thiomorpholine and thiomorpholine S,S-dioxide.

A “4- to 7-membered heterocyclyl group optionally fused to a 4- to7-membered carbocyclyl or heterocyclyl group”, unless otherwise stated,includes saturated and fully or partially unsaturated, monocyclic orbicyclic rings, each ring containing 4, 5, 6 or 7 atoms and at least onering atom of one ring is a heteroatom selected from nitrogen, oxygen andsulphur, and which may, unless otherwise specified, be carbon ornitrogen linked. Suitable “4- to 7-membered heterocyclyl groupoptionally fused to a 4- to 7-membered carbocyclyl or heterocyclylgroup” which may comprise at least one ring heteroatom selected fromnitrogen, oxygen and sulphur include azetidine, benzfuran,benzimidazole, benzthiophene, gamma-butyrolactone, diazepine, dioxolane,dioxane, dihydro-oxazine, dihydrothiophene, dithiolan, furan,hexahydroazepine, imidazole, imidazoline, imidazolidine, indazole,indole, isothiazole, isoxazole, morpholine, oxadiazole, oxazine,oxazole, oxetane, piperidine, piperazine, alpha-pyran, gamma-pyran,pyrazine, pyrazolidine, pyrazole, pyrazoline, pyridazine, pyridine,pyrimidine, pyrrole, pyrrolidine, pyrroline, quinazoline, quinoline,tetrahydrofuran, tetrahydrofuranone, tetrahydropyran,tetrahydroquinoline, tetrazine, tetrazole, thiadiazole, thiazole,thiolan, thiomorpholine, thiomorpholine S,S-dioxide, thiophene andtriazine.

For the avoidance of doubt, where it is indicated that substituents maycarry further substituents for example in definitions of terms such as“a C₁-C₃alkyl group optionally substituted by one or more substituentsselected from C₁-C₃alkoxy, C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁴R⁵ (eachof which may be optionally substituted by one or more substituentsselected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino(—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl)”, itis understood that atoms, such as carbon atoms that may be capable ofcarrying optionally substituents by replacement of hydrogen radicals, inthe groups C₁-C₃alkoxy, C₃-cycloalkyl, C₁-C₃alkylthio and —NR⁴R⁵(irrespective of any additional substituents defined in the definitionsof R⁴ or R⁵) may be substituted by one or more substituents selectedfrom halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl. For example,R⁴ or R⁵ may also be substituted by one or more substituents selectedfrom halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess FGFR inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess FGFR inhibitory activity. For example,the compound of formula (IA) is a tautomer of the compound of formula(I).

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms that possess FGFR inhibitory activity.

Particular values of variable groups are as follows. Such values may beused where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter.

In a further embodiment of the invention, A represents a furyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phenyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolylring.

In a further embodiment of the invention, A represents a furyl, phenyl,pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl or thiazolyl ring.

In a further embodiment of the invention, A represents a furyl, phenyl,pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl or thienyl ring.

In a further embodiment of the invention, A represents a furyl, phenyl,pyrazinyl, pyridazinyl, pyridyl, or pyrimidinyl ring.

In a further aspect of the invention, A represents a furyl, phenyl,pyridyl or pyrimidinyl ring.

In a further aspect of the invention, A represents a furyl, phenyl orpyridyl ring.

In a further aspect of the invention, A represents a furyl or phenylring.

In a further aspect of the invention, A represents a phenyl ring.

In a further embodiment of the invention B represents a furyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phenyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolylring.

In a further embodiment of the invention B represents a furyl,isothiazolyl, isoxazolyl, oxadiazolyl, phenyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl or thienyl ring.

In a further embodiment of the invention, B represents a furyl, phenyl,pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl or thiazolyl ring.

In a further embodiment of the invention, B represents a furyl, phenyl,pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl or thienyl ring.

In a further embodiment of the invention B represents a phenyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl or pyrimidinyl ring.

In a further embodiment of the invention B represents a phenyl,pyrazinyl, pyridyl, thienyl or pyrimidinyl ring.

In a further aspect of the invention B represents a pyridyl, pyrimidinylor phenyl ring.

In a further embodiment of the invention B represents a phenyl,pyrazinyl, thienyl or pyrimidinyl ring.

In a further aspect of the invention B represents a phenyl ring.

In one embodiment of the invention, each R¹ independently represents ahalogen; a hydroxyl group; a C₁-C₃alkyl group optionally substituted byone or more substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally substituted byone or more substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen and hydroxyl; a C₁-C₃alkoxy group optionallysubstituted by one or more substituents selected from C₁-C₃alkoxy,C₃-cycloalkyl, —NR¹⁴R¹⁵, (each of which may be optionally substituted byone or more substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen and hydroxyl; or a —CONR²⁰R²¹ group.

In a further embodiment of the invention, each R¹ independentlyrepresents a halogen; a hydroxyl group; a C₁-C₃alkyl group optionallysubstituted by one or more substituents selected from C₁-C₃alkoxy,C₃-cycloalkyl, C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionallysubstituted by one or more substituents selected from halogen,C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;a C₁-C₃alkoxy group optionally substituted by one or more substituentsselected from C₁-C₃alkoxy, C₃-cycloalkyl, —NR¹⁴R¹⁵, (each of which maybe optionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;a —CONR²⁰R²¹ group; or two adjacent R¹ groups together with the atoms towhich they are attached form a 4- to 7-membered carbocyclyl orheterocyclyl ring optionally substituted by one or more substituentsselected from C₁-C₃alkyl, C₁-C₃alkoxy, C₃-cycloalkyl, C₁-C₃alkylthio,—NR²⁷R²⁸ (each of which may be optionally substituted by one or moresubstituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen and hydroxyl.

In a further embodiment of the invention, each R¹ independentlyrepresents a halogen; a hydroxyl group; a C₁-C₃alkoxy group optionallysubstituted by one or more substituents selected from C₁-C₃alkoxy,C₃-cycloalkyl, —NR¹⁴R¹⁵ (each of which may be optionally substituted byone or more substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen and hydroxyl; or a —CONR²⁰R²¹ group.

In a further embodiment of the invention, each R¹ independentlyrepresents a C₁-C₃alkoxy group optionally substituted by one or moresubstituents selected from C₁-C₃alkoxy, C₃-cycloalkyl, —NR¹⁴R¹⁵ (each ofwhich may be optionally substituted by one or more substituents selectedfrom halogen, C₁-C₃alkyl, C₁-C₃alkoxy, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In a further embodiment of the invention, each R¹ independentlyrepresents a C₁-C₃alkoxy group optionally substituted by one or moresubstituents selected from methoxy, —N(Me)₂ and hydroxyl.

In a further additional aspect of the invention each R¹ independentlyrepresents a —CONR²⁰R²¹ group.

In a further additional aspect of the invention each R¹ independentlyrepresents a methoxy group; —OCH₂CH₂OMe; —CH₂NMe₂ or two adjacent R¹groups together form an —OCH₂O— bridge.

In a further additional aspect of the invention each R¹ independentlyrepresents a hydroxyl group; —CONH₂; —CONHMe; —CONMe₂ or a methoxygroup.

In a further additional aspect of the invention each R¹ independentlyrepresents —CONHMe or a methoxy group.

In a further additional aspect of the invention R¹ represents —CONHMe.

In a further additional aspect of the invention R¹ represents methoxy.

In another embodiment of the invention, each R² independently representsa —NR³⁶R³⁷ group; a C₁-C₆alkyl group optionally substituted by one ormore substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,C₁-C₆alkylthio, —NR⁴³R⁴⁴, (each of which may be optionally substitutedby one or more substituents selected from halogen, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl and a 4- to7-membered heterocyclyl group optionally substituted by one or moresubstituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl), halogen, hydroxyl,and a 4- to 7-membered heterocyclyl group optionally fused to a 4- to7-membered carbocyclyl or heterocyclyl group optionally substituted byone or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl; a 4- to 7-membered heterocyclyl group optionally fused to a 4-to 7-membered carbocyclyl or heterocyclyl group and optionallysubstituted by one or more substituents selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆alkylcarbonyl,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, cyano, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen,oxo, hydroxyl and a 4- to 7-membered heterocyclyl group optionallysubstituted by one or more substituents selected from C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each ofwhich may be optionally substituted by one or more substituents selectedfrom halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl; or a C₁-C₆alkoxy group optionally substituted by one or moresubstituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl, —NR⁶²R⁶³ (eachof which may be optionally substituted by one or more substituentsselected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl anda 4- to 7-membered heterocyclyl group optionally substituted by one ormore substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl.

In another embodiment of the invention, each R² independently representsa —NR³⁶R³⁷ group; a C₁-C₆alkyl group optionally substituted by one ormore substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,C₁-C₆alkylthio, —NR⁴³R⁴⁴, (each of which may be optionally substitutedby one or more substituents selected from halogen, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl and a 4- to7-membered heterocyclyl group optionally substituted by one or moresubstituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl), halogen, hydroxyl,and a 4- to 7-membered heterocyclyl group optionally fused to a 4- to7-membered carbocyclyl or heterocyclyl group optionally substituted byone or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl; a 4- to 7-membered heterocyclyl group optionally fused to a 4-to 7-membered carbocyclyl or heterocyclyl group and optionallysubstituted by one or more substituents selected from C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each ofwhich may be optionally substituted by one or more substituents selectedfrom halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen,hydroxyl and a 4- to 7-membered heterocyclyl group optionallysubstituted by one or more substituents selected from C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each ofwhich may be optionally substituted by one or more substituents selectedfrom halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl; or a C₁-C₆alkoxy group optionally substituted by one or moresubstituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl, —NR⁶²R⁶³ (eachof which may be optionally substituted by one or more substituentsselected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl anda 4- to 7-membered heterocyclyl group optionally substituted by one ormore substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl.

In a further aspect of the invention, each R² independently represents ahydroxyl group; a halogen; a cyano group; a —CO₂R²⁹ group; a —CONR³⁰R³¹group; a —NR³²COR³³ group; a —NR³⁴CO₂R³⁵ group; a —NR³⁶R³⁷ group; a—SO₂R³⁸ group; a —SO₂NR³⁹R⁴⁰ group; a —NR⁴¹SO₂R⁴² group; a C₁-C₆alkylgroup optionally substituted by one or more substituents selected fromC₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴³R⁴⁴, (each of whichmay be optionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino(—NH₂), mono- and di-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyland a 4- to 7-membered heterocyclyl group optionally substituted by oneor more substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl), halogen, hydroxyl,and a 4- to 7-membered heterocyclyl group optionally fused to a 4- to7-membered carbocyclyl or heterocyclyl group optionally substituted byone or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), cyano, halogenand hydroxyl; a 4- to 7-membered heterocyclyl group optionally fused toa 4- to 7-membered carbocyclyl or heterocyclyl group and optionallysubstituted by one or more substituents selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆alkylcarbonyl,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, cyano, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen,oxo, hydroxyl and a 4- to 7-membered heterocyclyl group optionallysubstituted by one or more substituents selected from C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each ofwhich may be optionally substituted by one or more substituents selectedfrom halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂),mono- and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl; or a C₁-C₆alkoxy group optionally substituted by one or moresubstituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl, —NR⁶²R⁶³ (eachof which may be optionally substituted by one or more substituentsselected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl anda 4- to 7-membered heterocyclyl group optionally substituted by one ormore substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl.

In a further aspect of the invention, each R² independently represents ahydroxyl group; a halogen; a cyano group; a —CO₂R²⁹ group; a —CONR³⁰R³¹group; a —NR³²COR³³ group; a —NR³⁴CO₂R³⁵ group; a —NR³⁶R³⁷ group; a—SO₂R³⁸ group; a —SO₂NR³⁹R⁴⁰ group; a —NR⁴¹SO₂R⁴² group; a C₁-C₆alkylgroup optionally substituted by one or more substituents selected fromC₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴³R⁴⁴, (each of whichmay be optionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino(—NH₂), mono- and di-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyland a 4- to 7-membered heterocyclyl group optionally substituted by oneor more substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl), halogen, hydroxyl,and a 4- to 7-membered heterocyclyl group optionally fused to a 4- to7-membered carbocyclyl or heterocyclyl group optionally substituted byone or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), cyano, halogenand hydroxyl; a 4- to 7-membered heterocyclyl group optionally fused toa 4- to 7-membered carbocyclyl or heterocyclyl group and optionallysubstituted by one or more substituents selected from C₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆alkylcarbonyl, C₃-C₆cycloalkyl, C₁-C₆alkylthio,—NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may be optionally substituted by one ormore substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen, hydroxyl and a 4- to 7-membered heterocyclylgroup optionally substituted by one or more substituents selected fromC₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰,—SO₂R⁶¹ (each of which may be optionally substituted by one or moresubstituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen and hydroxyl; or a C₁-C₆alkoxy groupoptionally substituted by one or more substituents selected fromC₁-C₆alkoxy, C₃-C₆cycloalkyl, —NR⁶²R⁶³ (each of which may be optionallysubstituted by one or more substituents selected from halogen,C₁-C₃alkyl, C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to 7-memberedheterocyclyl group optionally substituted by one or more substituentsselected from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio,—NR⁶⁴R⁶⁵ (each of which may be optionally substituted by one or moresubstituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen and hydroxyl.

In a further aspect of the invention, each R² independently represents a—NR³⁶R³⁷ group; a C₁-C₆alkyl group optionally substituted by one or moresubstituents selected from —NR⁴³R⁴⁴ (which may be optionally substitutedby one or more substituents selected from halogen, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl, trifluoromethyl and a morpholine,piperidine or piperazine optionally substituted by one or moresubstituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl), and a morpholine,piperidine or piperazine optionally substituted by one or moresubstituents selected from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of which may be optionallysubstituted by one or more substituents selected from halogen,C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono- anddi-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;or a morpholine, piperidine or piperazine optionally substituted by oneor more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyland a 4- to 7-membered heterocyclyl group optionally substituted by oneor more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl.

In a further aspect of the invention, each R² independently represents amethyl or a methoxy group optionally substituted by a morpholine,piperidine or piperazine group each optionally substituted by one ormore substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyland a 4- to 7-membered heterocyclyl group optionally substituted by oneor more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl.

In a further aspect of the invention, each R² independently represents amorpholine, piperidine or piperazine optionally substituted by one ormore substituents selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₆alkylcarbonyl, C₃-C₆cycloalkyl, C₁-C₆alkylthio,—NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may be optionally substituted by one ormore substituents selected from halogen, cyano, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen, oxo, hydroxyl and a 4- to 7-memberedheterocyclyl group optionally substituted by one or more substituentsselected from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio,—NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of which may be optionally substituted by one ormore substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl andtrifluoromethyl), halogen and hydroxyl.

In a further aspect of the invention, each R² independently represents amorpholine, piperidine or piperazine optionally substituted by one ormore substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyland a 4- to 7-membered heterocyclyl group optionally substituted by oneor more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of which may beoptionally substituted by one or more substituents selected fromhalogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl), halogen andhydroxyl.

In a further aspect of the invention, each R² independently represents a—Cl; —F; —I; —OH; —CN; —CH₃; —CH₂OH; —CH₂N(CH₃)₂; —CH₂CH(CH₃)NH₂; —OCH₃;—OCH₂CH₂OH; —OCH₂CH₂OCH₂CH₃; —SO₂CH₃; —N(CH₃)₂; —NHPh; —NHCH₂C≡CH;—NHCH₂CH₃; —NHCH₂CH₂N(CH₃)₂; —NHCO₂CH₂CH═CH₂; —NHCOCH₃; —NHCOH; —NHCOPh;—CONH₂; —NHSO₂Me; —SO₂N(CH₃)₂; —CO₂H; —CO₂CH₃; —CO₂CH₂CH₃;

group.

In a further aspect of the invention, each R² independently represents a—Cl; —F; —I; —OH; —CN; —CH₃; —CH₂OH; —CH₂N(CH₃)₂; —CH₂CH(CH₃)NH₂; —OCH₃;—OCH₂CH₂OH; —OCH₂CH₂OCH₂CH₃; —SO₂CH₃; —OCH₂CH₂OH; —N(CH₃)₂; —NHPh;—NHCH₂C≡CH; —NHCH₂CH₃; —NHCH₂CH₂N(CH₃)₂; —NHCO₂CH₂CH═CH₂; —NHCOCH₃;—NHCOH; —NHCOPh; —CONH₂; —NHSO₂Me; —SO₂N(CH₃)₂; —CO₂H; —CO₂CH₃;—CO₂CH₂CH₃;

group.

In a further aspect of the invention, each R² independently represents a—Cl; —F; —I; —OH; —CN; —CH₃; —CH₂OH; —CH₂N(CH₃)₂; —CH₂CH(CH₃)NH₂; —OCH₃;—OCH₂CH₂OH; —OCH₂CH₂OCH₂CH₃; —SO₂CH₃; —OCH₂CH₂OH; —N(CH₃)₂; —NHPh;—NHCH₂C≡CH; —NHCH₂CH₃; —NHCH₂CH₂N(CH₃)₂; —NHCO₂CH₂CH═CH₂; —NHCOCH₃;—NHCOH; —NHCOPh; —CONH₂; —NHSO₂Me; —SO₂N(CH₃)₂; —CO₂H; —CO₂CH₃;—CO₂CH₂CH₃;

group.

In a further aspect of the invention, each R² independently represents a—OMe; —OCH₂CH₂OCH₂CH₃; —OCH₂CH₂OH; —CH₂N(CH₃)₂; —NHCH₂CH₂N(CH₃)₂;

group.

In a further aspect of the invention, each R² independently represents a—NHCH₂CH₂N(CH₃)₂;

group.

In a further aspect of the invention, each R² independently represents a

group.

In a further aspect of the invention, each R² independently represents a

group.

In a further aspect of the invention, each R² independently represents a

group.

In a further aspect of the invention, R² represents a

group.

In a further aspect of the invention, R² represents a

group.

In a further aspect of the invention, R² represents

wherein

-   -   G¹ is C or N,    -   n is 1 or 2,    -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently        selected from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl,        C₃-C₅cycloalkyl, (each of which may be optionally substituted by        one or more substituents selected from halogen, C₁-C₂alkyl,        C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and        di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl), hydrogen,        halogen and hydroxyl, or    -   R^(C1) and R^(C2) and/or R^(C3) and R^(C4) together with the        atom to which they are attached form a 3- to 6-membered        carbocyclic or heterocyclic ring optionally substituted by one        or more substituents selected from halogen, C₁-C₂alkyl,        C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and        di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl, or    -   R^(C1) and R^(C3) together with the atoms to which they are        attached and the nitrogen atom to which the R^(N1) group is        attached form a 5- to 7-membered carbocyclic or heterocyclic        ring optionally substituted by one or more substituents selected        from halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio, amino        (—NH₂), mono- and di-C₁-C₂alkylamino, hydroxyl and        trifluoromethyl, and    -   R^(N1) is selected from selected from C₁-C₄alkyl, C₂-C₄alkenyl,        C₂-C₄alkynyl, C₃-C₆cycloalkyl, (each of which may be optionally        substituted by one or more substituents selected from cyano,        halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂),        mono- and di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl),        hydrogen and a 4- to 7-membered heterocyclyl group optionally        substituted by one or more substituents selected from        C₁-C₃alkyl, C₁-C₃alkoxy, C₃-C₅cycloalkyl, C₁-C₃alkylthio,        —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of which may be optionally substituted        by one or more substituents selected from halogen, C₁-C₂alkyl,        C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and        di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl), halogen and        hydroxyl, or    -   R^(N1) and R^(C4) together with the atoms to which they are        attached form a 4- to 7-membered heterocyclyl ring optionally        substituted by one or more substituents selected from        C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, C₁-C₃alkoxy,        C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which        may be optionally substituted by one or more substituents        selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio,        amino (—NH₂), mono- and di-C₁-C₂alkylamino, hydroxyl and        trifluoromethyl), halogen, hydroxyl.

In a further aspect of the invention, R² independently represents

wherein

-   -   G¹ is C or N,    -   n is 1 or 2,    -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently        selected from hydrogen, methyl, ethyl, hydroxymethyl,        hydroxyethyl, methoxymethyl, methoxyethyl, 2,2,2-trifluoroethyl,        or    -   R^(C3) and R^(C4) together with the atom to which they are        attached form a 3- to 5-membered carbocyclic ring, and    -   R^(N1) is selected from selected from C₁-C₂alkyl, C₂-C₃alkenyl,        C₂-C₃alkynyl, C₃-C₅cycloalkyl, (each of which may be optionally        substituted by one or more substituents selected from halogen,        C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and        di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl) and hydrogen,        or    -   R^(N1) and R^(C4) together with the atoms to which they are        attached form a 4- to 7-membered heterocyclyl ring.

In a further aspect of the invention, R² independently represents

wherein

-   -   G¹ is C or N,    -   n is 1 or 2,    -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently        selected from hydrogen, methyl, ethyl, hydroxymethyl,        hydroxyethyl, methoxymethyl, methoxyethyl, 2,2,2-trifluoroethyl,        or    -   R^(C3) and R^(C4) together with the atom to which they are        attached form a cyclopropyl ring, and    -   R^(N1) is selected from selected from hydrogen, methyl, ethyl,        methoxyethyl, ethoxyethyl, hydroxyethyl propenyl, propynyl,        propyl, i-propyl, —CH(CH₃)CH₂OH, cyclopropyl, cyclobutyl,        cyclopentyl, or    -   R^(N1) and R^(C4) together with the atoms to which they are        attached form a 5- or 6-membered heterocyclyl ring.

In a further aspect of the invention, R² independently represents

wherein

-   -   G¹ is C or N,    -   n is 1 or 2,    -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently        selected from hydrogen, methyl, ethyl, hydroxymethyl,        hydroxyethyl, methoxymethyl, methoxyethyl, 2,2,2-trifluoroethyl,        or    -   R^(C3) and R^(C4) together with the atom to which they are        attached form a cyclopropyl ring, and    -   R^(N1) is selected from selected from hydrogen, methyl, ethyl,        methoxyethyl, ethoxyethyl, hydroxyethyl propenyl, propynyl,        i-propyl, —CH(CH₃)CH₂OH, cyclopropyl, cyclobutyl, cyclopentyl,        or    -   R^(N1) and R^(C4) together with the atoms to which they are        attached form a 5- or 6-membered heterocyclyl ring.

In a further aspect of the invention R³ represent hydrogen.

In a further embodiment of the invention X represents CH₂ or O.

In a further embodiment of the invention Y represents CH₂.

In a further embodiment of the invention a is 0, 1 or 2.

In a further embodiment of the invention b is 0, 1 or 2.

In a further aspect of the invention, b is 1.

In a further aspect of the invention, -A-(R¹)_(a) represents a

group.

In a further aspect of the invention, -A-(R¹)_(a) represents a

group.

In a further aspect of the invention, —B—(R²)_(b) represents a

group.

In a further aspect of the invention, —B—(R²)_(b) represents a

group.

In a further aspect of the invention, —B—(R²)_(b) represents a

group.

In an embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents a furyl, imidazolyl, isothiazolyl, isoxazolyl,        oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl,        thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolyl ring;    -   ring B represents a furyl, imidazolyl, isothiazolyl, isoxazolyl,        oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl,        thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   each R² independently represents        -   a —NR³⁶R³⁷ group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴³R⁴⁴, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl trifluoromethyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- and            di-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl),            halogen, hydroxyl, and a 4- to 7-membered heterocyclyl group            optionally fused to a 4- to 7-membered carbocyclyl or            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;        -   a 4- to 7-membered heterocyclyl group optionally fused to a            4- to 7-membered carbocyclyl or heterocyclyl group and            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,            C₁-C₆alkylcarbonyl, C₃-C₆cycloalkyl, C₁-C₆alkylthio,            —NR⁵⁶R⁵⁷ SO₂R⁵⁸ (each of which may be optionally substituted            by one or more substituents selected from halogen, cyano,            C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-            and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl),            halogen, oxo, hydroxyl and a 4- to 7-membered heterocyclyl            group optionally substituted by one or more substituents            selected from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl, or        -   a C₁-C₆alkoxy group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            —NR⁶²R⁶³ (each of which may be optionally substituted by one            or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen;    -   X represents CH₂ or O;    -   Y represents CH₂;    -   a is 0, 1 or 2; and    -   b is 0, 1 or 2.

In an embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents a furyl, imidazolyl, isothiazolyl, isoxazolyl,        oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl,        thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolyl ring;    -   ring B represents a furyl, imidazolyl, isothiazolyl, isoxazolyl,        oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl,        thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   each R² independently represents        -   a —NR³⁶R³⁷ group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴³R⁴⁴, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl trifluoromethyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- and            di-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl),            halogen, hydroxyl, and a 4- to 7-membered heterocyclyl group            optionally fused to a 4- to 7-membered carbocyclyl or            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;        -   a 4- to 7-membered heterocyclyl group optionally fused to a            4- to 7-membered carbocyclyl or heterocyclyl group and            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, hydroxyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a C₁-C₆alkoxy group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            —NR⁶²R⁶³ (each of which may be optionally substituted by one            or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen;    -   X represents CH₂ or O;    -   Y represents CH₂;    -   a is 0, 1 or 2; and    -   b is 0, 1 or 2.

In an embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents a furyl, imidazolyl, isothiazolyl, isoxazolyl,        oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl,        thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolyl ring;    -   ring B represents a furyl, imidazolyl, isothiazolyl, isoxazolyl,        oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl,        pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl,        thiadiazolyl, thiazolyl, thienyl, trazinyl or triazolyl ring;    -   each R¹ independently represents        -   a halogen,        -   a hydroxyl group,        -   a C₁-C₃alkyl group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            C₁-C₃alkylthio, —NR⁴R⁵ (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl,        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   a —CONR²⁰R²¹ group, or        -   two adjacent R¹ groups together with the atoms to which they            are attached form a 4- to 7-membered carbocyclyl or            heterocyclyl ring optionally substituted by one or more            substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-cycloalkyl, C₁-C₃alkylthio, —NR²⁷R²⁸ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   each R² independently represents        -   a hydroxyl group,        -   a halogen,        -   a cyano group,        -   a —CO₂R²⁹ group,        -   a —CONR³⁰R³¹ group,        -   a —NR³²COR³³ group,        -   a —NR³⁴CO₂R³⁵ group,        -   a —NR³⁶R³⁷ group,        -   a —SO₂R³⁸ group,        -   a —SO₂NR³⁹R⁴⁰ group,        -   a —NR⁴¹SO₂R⁴² group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴³R⁴⁴, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl trifluoromethyl and a 4- to 7-membered            heterocyclyl group optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂), mono- and            di-C₁-C₃alkylamino, cyano, hydroxyl trifluoromethyl),            halogen, hydroxyl, and a 4- to 7-membered heterocyclyl group            optionally fused to a 4- to 7-membered carbocyclyl or            heterocyclyl group optionally substituted by one or more            substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), cyano, halogen and hydroxyl,        -   a 4- to 7-membered heterocyclyl group optionally fused to a            4- to 7-membered carbocyclyl or heterocyclyl group and            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylcarbonyl,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a C₁-C₆alkoxy group optionally substituted by one or more            substituents selected from C₁-C₆alkoxy, C₃-C₆cycloalkyl,            —NR⁶²R⁶³ (each of which may be optionally substituted by one            or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁶⁴R⁶⁵ (each of which may            be optionally substituted by one or more substituents            selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen;    -   X represents CH₂ or O;    -   Y represents CH₂;    -   a is 0, 1 or 2; and    -   b is 0, 1 or 2.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl or thienyl ring;    -   ring B represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl or thienyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   each R² independently represents        -   a —NR³⁶R³⁷ group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from —NR⁴³R⁴⁴ (which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl, trifluoromethyl and a morpholine,            piperidine or piperazine optionally substituted by one or            more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂),            mono- and di-C₁-C₃alkylamino, cyano, hydroxyl            trifluoromethyl), and a morpholine, piperidine or piperazine            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl, or        -   a morpholine, piperidine or piperazine optionally            substituted by one or more substituents selected from            C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,            C₁-C₆alkylcarbonyl, C₃-C₆cycloalkyl, C₁-C₆alkylthio,            —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of which may be optionally            substituted by one or more substituents selected from            halogen, cyano, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            amino (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen, oxo, hydroxyl and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₆alkyl, C₁-C₆alkoxy,            C₃-C₆cycloalkyl, C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy,            C₁-C₃alkylthio, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen;    -   X represents CH₂ or O;    -   Y represents CH₂;    -   a is 0, 1 or 2; and    -   b is 0, 1 or 2.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl or thienyl ring;    -   ring B represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl or thienyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   each R² independently represents        -   a —NR³⁶R³⁷ group,        -   a C₁-C₆alkyl group optionally substituted by one or more            substituents selected from —NR⁴³R⁴⁴ (which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio,            C₃-C₆cycloalkyl, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            cyano, hydroxyl, trifluoromethyl and a morpholine,            piperidine or piperazine optionally substituted by one or            more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, C₁-C₃alkylthio, C₃-C₆cycloalkyl, amino (—NH₂),            mono- and di-C₁-C₃alkylamino, cyano, hydroxyl            trifluoromethyl), and a morpholine, piperidine or piperazine            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁴⁵R⁴⁶, —CO₂R⁴⁷ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl, or        -   a morpholine, piperidine or piperazine optionally            substituted by one or more substituents selected from            C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₁-C₆alkylthio,            —NR⁵⁶R⁵⁷ SO₂R⁵⁸ (each of which may be optionally substituted            by one or more substituents selected from halogen,            C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino (—NH₂), mono-            and di-C₁-C₃alkylamino, hydroxyl and trifluoromethyl),            halogen, hydroxyl and a 4- to 7-membered heterocyclyl group            optionally substituted by one or more substituents selected            from C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,            C₁-C₆alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, amino            (—NH₂), mono- and di-C₁-C₃alkylamino, hydroxyl and            trifluoromethyl), halogen and hydroxyl;    -   R³ represents hydrogen;    -   X represents CH₂ or O;    -   Y represents CH₂;    -   a is 0, 1 or 2; and    -   b is 0, 1 or 2.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents furyl, phenyl or pyridyl ring;    -   ring B represents phenyl, pyrazinyl, pyridyl, pyrimidinyl or        thienyl ring;    -   each R¹ independently represents        -   a methoxy group, —OCH₂CH₂Ome, —CH₂NMe₂ or two adjacent R¹            groups together form an —OCH₂O— bridge;    -   each R² independently represents        -   a —Cl, —F, —I, —OH, —CN, —CH₃, —CH₂OH, —CH₂N(CH₃)₂,            —CH₂CH(CH₃)NH₂, —OCH₃, —OCH₂CH₂OH, —OCH₂CH₂OCH₂CH₃, —SO₂CH₃,            —N(CH₃)₂, —NHPh, —NHCH₂C≡CH, —NHCH₂CH₃, —NHCH₂CH₂N(CH₃)₂,            —NHCO₂CH₂CH═CH₂, —NHCOCH₃, —NHCOH, —NHCOPh, —CONH₂,            —NHSO₂Me, —SO₂N(CH₃)₂, —CO₂H, —CO₂CH₃, —CO₂CH₂CH₃,

-   -   -    group;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂;

    -   a is 0, 1 or 2; and

    -   b is 0, 1 or 2.

In a further aspect of the invention, there is provided a compound offormula (I), or pharmaceutically acceptable salts thereof, wherein:

-   -   ring A represents a furyl, phenyl, pyridyl or pyrimidinyl ring;    -   ring B represents a phenyl, pyridyl, pyrimidinyl or thienyl        ring;    -   each R¹ independently represents —CONHMe or a methoxy group;    -   R² represents a

group;

-   -   X represents CH₂ or O;    -   Y represents CH₂;    -   a is 0, 1 or 2; and    -   b is 1.

In a further aspect of the invention, there is provided a compound offormula (I), or pharmaceutically acceptable salts thereof, wherein:

-   -   ring A represents furyl, phenyl, pyridyl or pyrimidinyl ring;    -   ring B represents a phenyl, pyridyl or pyrimidinyl ring;    -   R¹ represents methoxy;    -   R² represents a

-   -    or group;    -   X represents CH₂ or O;    -   a is 0, 1 or 2; and    -   b is 1,        or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   -A-(R¹)_(a) represents a

-   -    or group;    -   ring B represents phenyl, pyrazinyl, pyridyl, pyrimidinyl or        thienyl ring;    -   each R² independently represents        -   a —OMe, —OCH₂CH₂OCH₂CH₃, —OCH₂CH₂OH, —CH₂N(CH₃)₂,            —NHCH₂CH₂N(CH₃)₂,

-   -   -    group;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂;

    -   b is 1.

In a further aspect of the invention, there is provided a compound offormula (I), or pharmaceutically acceptable salts thereof, wherein:

-   -   -A-(R¹)_(a) represents a

-   -    group;    -   —B—(R²)_(b) represents a

-   -    group; and    -   X represents CH₂ or O,        or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention, there is provided a compound offormula (I), or pharmaceutically acceptable salts thereof, wherein:

-   -   -A-(R¹)_(a) represents

-   -    a group;    -   —B—(R²)_(b) represents a

-   -    group; and    -   X represents CH₂,        or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention, there is provided a compound offormula (I), or pharmaceutically acceptable salts thereof, wherein:

-   -   -A-(R¹)_(a) represents a

-   -    group;    -   —B—(R²)_(b) represents a

-   -    group; and    -   X represents O,        or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention, there is provided a compound offormula (I), or pharmaceutically acceptable salts thereof, wherein:

-   -   -A-(R¹)_(a) represents a

-   -    group; and    -   —B—(R²)_(b) represents a

group.

In a further aspect of the invention, there is provided a compound offormula (I), or pharmaceutically acceptable salts thereof, wherein:

-   -   -A-(R¹)_(a) represents a

-   -    group; and    -   —B—(R²)_(b) represents a

group.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl, thienyl or thiazolyl ring;    -   ring B represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl, thienyl or thiazolyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   R² represents

-   -   -   wherein        -   G¹ is C or N,        -   n is 1 or 2,        -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently            selected from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl,            C₃-C₅cycloalkyl, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio, amino            (—NH₂), mono- and di-C₁-C₂alkylamino, hydroxyl and            trifluoromethyl), hydrogen, halogen and hydroxyl, or        -   R^(C1) and R^(C2) and/or R^(C3) and R^(C4) together with the            atom to which they are attached form a 3- to 6-membered            carbocyclic or heterocyclic ring optionally substituted by            one or more substituents selected from halogen, C₁-C₂alkyl,            C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and            di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl, or        -   R^(C1) and R^(C3) together with the atoms to which they are            attached and the nitrogen atom to which the R^(N1) group is            attached form a 5- to 7-membered carbocyclic or heterocyclic            ring optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl, and        -   R^(N1) is selected from selected from C₁-C₄alkyl,            C₂-C₄alkenyl, C₂-C₄alkynyl, C₃-C₆cycloalkyl, (each of which            may be optionally substituted by one or more substituents            selected from cyano, halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), hydrogen and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   R^(N1) and R^(C4) together with the atoms to which they are            attached form a 4- to 7-membered heterocyclyl ring            optionally substituted by one or more substituents selected            from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂;

    -   a is 0, 1 or 2; and

    -   b is 1.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl or thienyl ring;    -   ring B represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl or thienyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   R² represents

-   -   -   wherein        -   G¹ is C or N,        -   n is 1 or 2,        -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently            selected from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl,            C₃-C₅cycloalkyl, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio, amino            (—NH₂), mono- and di-C₁-C₂alkylamino, hydroxyl and            trifluoromethyl), hydrogen, halogen and hydroxyl, or        -   R^(C1) and R^(C2) and/or R^(C3) and R^(C4) together with the            atom to which they are attached form a 3- to 6-membered            carbocyclic or heterocyclic ring optionally substituted by            one or more substituents selected from halogen, C₁-C₂alkyl,            C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and            di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl, or        -   R^(C1) and R^(C3) together with the atoms to which they are            attached and the nitrogen atom to which the R^(N1) group is            attached form a 5- to 7-membered carbocyclic or heterocyclic            ring optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl, and        -   R^(N1) is selected from selected from C₁-C₄alkyl,            C₂-C₄alkenyl, C₂-C₄alkynyl, C₃-C₆cycloalkyl, (each of which            may be optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), hydrogen and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   R^(N1) and R^(C4) together with the atoms to which they are            attached form a 4- to 7-membered heterocyclyl ring            optionally substituted by one or more substituents selected            from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂;

    -   a is 0, 1 or 2; and

    -   b is 1.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents furyl, phenyl or pyridyl ring;    -   ring B represents phenyl, pyrazinyl, pyridyl, pyrimidinyl or        thienyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   R² represents

-   -   -   wherein        -   G¹ is C or N,        -   n is 1 or 2, R^(C1), R^(C2), R^(C3) and R^(C4) are each            independently selected from C₁-C₃alkyl, C₂-C₃alkenyl,            C₂-C₃alkynyl, C₃-C₅cycloalkyl, (each of which may be            optionally substituted by one or more substituents selected            from halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio, amino            (—NH₂), mono- and di-C₁-C₂alkylamino, hydroxyl and            trifluoromethyl), hydrogen, halogen and hydroxyl, or        -   R^(C1) and R^(C2) and/or R^(C3) and R^(C4) together with the            atom to which they are attached form a 3- to 6-membered            carbocyclic or heterocyclic ring optionally substituted by            one or more substituents selected from halogen, C₁-C₂alkyl,            C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and            di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl, or        -   R^(C1) and R^(C3) together with the atoms to which they are            attached and the nitrogen atom to which the R^(N1) group is            attached form a 5- to 7-membered carbocyclic or heterocyclic            ring optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl, and        -   R^(N1) is selected from selected from C₁-C₄alkyl,            C₂-C₄alkenyl, C₂-C₄alkynyl, C₃-C₆cycloalkyl, (each of which            may be optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), hydrogen and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   R^(N1) and R^(C4) together with the atoms to which they are            attached form a 4- to 7-membered heterocyclyl ring            optionally substituted by one or more substituents selected            from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂;

    -   a is 0, 1 or 2; and

    -   b is 1.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents phenyl ring;    -   ring B represents phenyl, pyrazinyl, pyridyl, pyrimidinyl or        thienyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkoxy group optionally substituted by one or more            substituents selected from C₁-C₃alkoxy, C₃-cycloalkyl,            —NR¹⁴R¹⁵, (each of which may be optionally substituted by            one or more substituents selected from halogen, C₁-C₃alkyl,            C₁-C₃alkoxy, amino (—NH₂), mono- and di-C₁-C₃alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl, or        -   a —CONR²⁰R²¹ group;    -   R² represents

-   -   -   wherein        -   G¹ is C or N,        -   n is 1 or 2,        -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently            selected from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl,            C₃-C₅cycloalkyl, (each of which may be optionally            substituted by one or more substituents selected from            halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂alkylthio, amino            (—NH₂), mono- and di-C₁-C₂alkylamino, hydroxyl and            trifluoromethyl), hydrogen, halogen and hydroxyl, or        -   R^(C1) and R^(C2) and/or R^(C3) and R^(C4) together with the            atom to which they are attached form a 3- to 6-membered            carbocyclic or heterocyclic ring optionally substituted by            one or more substituents selected from halogen, C₁-C₂alkyl,            C₁-C₂alkoxy, C₁-C₂alkylthio, amino (—NH₂), mono- and            di-C₁-C₂alkylamino, hydroxyl and trifluoromethyl, or        -   R^(C1) and R^(C3) together with the atoms to which they are            attached and the nitrogen atom to which the R^(N1) group is            attached form a 5- to 7-membered carbocyclic or heterocyclic            ring optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl, and        -   R^(N1) is selected from selected from C₁-C₄alkyl,            C₂-C₄alkenyl, C₂-C₄alkynyl, C₃-C₆cycloalkyl, (each of which            may be optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), hydrogen and a 4- to            7-membered heterocyclyl group optionally substituted by one            or more substituents selected from C₁-C₃alkyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁹R⁶⁰, —SO₂R⁶¹ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen and hydroxyl,        -   or R^(N1) and R^(C4) together with the atoms to which they            are attached form a 4- to 7-membered heterocyclyl ring            optionally substituted by one or more substituents selected            from C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, C₁-C₃alkoxy,            C₃-C₅cycloalkyl, C₁-C₃alkylthio, —NR⁵⁶R⁵⁷, SO₂R⁵⁸ (each of            which may be optionally substituted by one or more            substituents selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl), halogen, hydroxyl;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂;

    -   a is 0, 1 or 2; and

    -   b is 1

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   ring A represents phenyl ring;    -   ring B represents furyl, phenyl, pyrazinyl, pyridazinyl,        pyridyl, pyrimidinyl or thienyl ring;    -   each R¹ independently represents        -   a C₁-C₃alkoxy group;    -   R² represents

-   -   -   wherein        -   G¹ is C or N,        -   n is 1 or 2,        -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently            selected from hydrogen, methyl, ethyl, hydroxymethyl,            hydroxyethyl, methoxymethyl, methoxyethyl,            2,2,2-trifluoroethyl, or        -   R^(C3) and R^(C4) together with the atom to which they are            attached form a 3- to 5-membered carbocyclic ring,        -   and        -   R^(N1) is selected from selected from C₁-C₂alkyl,            C₂-C₃alkenyl, C₂-C₃alkynyl, C₃-C₅cycloalkyl, (each of which            may be optionally substituted by one or more substituents            selected from halogen, C₁-C₂alkyl, C₁-C₂alkoxy,            C₁-C₂alkylthio, amino (—NH₂), mono- and di-C₁-C₂alkylamino,            hydroxyl and trifluoromethyl) and hydrogen, or        -   R^(N1) and R^(C4) together with the atoms to which they are            attached form a 4- to 7-membered heterocyclyl ring;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂;

    -   a is 0, 1 or 2; and

    -   b is 1.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   A(R¹)_(a) represents 3,5-dimethoxyphenyl;    -   ring B represents phenyl, pyrazinyl, pyrimidinyl or thienyl        ring;    -   R² represents

-   -   -   wherein        -   G¹ is C or N,        -   n is 1 or 2,        -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently            selected from hydrogen, methyl, ethyl, hydroxymethyl,            hydroxyethyl, methoxymethyl, methoxyethyl,            2,2,2-trifluoroethyl, or        -   R^(C3) and R^(C4) together with the atom to which they are            attached form a cyclopropyl ring,        -   and        -   R^(N1) is selected from selected from hydrogen, methyl,            ethyl, methoxyethyl, ethoxyethyl, hydroxyethyl, propenyl,            propynyl, propyl, i-propyl, —CH(CH₃)CH₂OH, cyclopropyl,            cyclobutyl, cyclopentyl, or        -   R^(N1) and R^(C4) together with the atoms to which they are            attached form a 5- or 6-membered heterocyclyl ring;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂; and

    -   b is 1.

In another embodiment of the invention, there is provided a subset ofcompounds of formula (I), or pharmaceutically acceptable salts thereof,wherein:

-   -   A(R¹)_(a) represents 3,5-dimethoxyphenyl;    -   ring B represents phenyl, pyrazinyl, pyrimidinyl or thienyl        ring;    -   R² represents

-   -   -   wherein        -   G¹ is C or N,        -   n is 1,        -   R^(C1), R^(C2), R^(C3) and R^(C4) are each independently            selected from hydrogen, methyl, ethyl, hydroxymethyl,            hydroxyethyl, methoxymethyl, methoxyethyl,            2,2,2-trifluoroethyl, or        -   R^(C3) and R^(C4) together with the atom to which they are            attached form a cyclopropyl ring,        -   and        -   R^(N1) is selected from selected from hydrogen, methyl,            ethyl, methoxyethyl, ethoxyethyl, hydroxyethyl, propenyl,            propynyl, i-propyl, —CH(CH₃)CH₂OH, cyclopropyl, cyclobutyl,            cyclopentyl, or        -   R^(N1) and R^(C4) together with the atoms to which they are            attached form a 5- or 6-membered heterocyclyl ring;

    -   R³ represents hydrogen;

    -   X represents CH₂ or O;

    -   Y represents CH₂; and

    -   b is 1.

In a further embodiment of the invention, only one of R^(C1) and R^(C2)or R^(C1) and R^(C3) or R^(C3) and R^(C4) or R^(N1) and R^(C4) togetherwith the atoms to which they are attached form a ring.

In a further embodiment of the invention, R^(C1) and R^(C2) togetherwith the atoms to which they are attached form a ring, and only one ofeither R^(C3) and R^(C4) or R^(N1) and R^(C4) may together with theatoms to which they are attached form a ring.

In a further embodiment of the invention R^(C1), R^(C2), R^(C3) andR^(C4) are each independently selected from hydrogen and methyl.

Examples of compounds of the invention include:

-   4-(4-methylpiperazin-1-yl)-N-(5-phenethyl-2H-pyrazol-3-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-methoxy-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-morpholin-4-yl-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3-fluoro-1-piperidyl)methyl]benzamide,-   N-[5-[2-[3-(2-Methoxyethoxy)phenyl]ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   4-(4-Methylpiperazin-1-yl)-N-[5-(2-pyridin-3-ylethyl)-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(2-furyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[2-(3-furyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-methyl-pyridine-3-carboxamide,-   6-Methoxy-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,-   N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-methylsulfonyl-benzamide,-   N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-methyl-pyrazine-2-carboxamide,-   N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(prop-2-ynylamino)pyridine-2-carboxamide,-   6-Ethylamino-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,-   4-Acetamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)pyrazine-2-carboxamide,-   4-benzamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   6-(2-methoxyethoxy)-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,-   4-cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzene-1,4-dicarboxamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-pyrazol-1-yl-benzamide,-   6-anilino-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,-   4-methanesulfonamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   4-(hydroxymethyl)-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   5-formamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-2-carboxamide,-   4-(dimethylsulfamoyl)-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   6-hydroxy-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-morpholin-4-yl-pyridine-3-carboxamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1,3-oxazol-5-yl)benzamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(tetrazol-1-yl)benzamide,-   prop-2-enyl    N-[5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridin-2-yl]carbamate,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1,2,4-triazol-1-yl)benzamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-pyrazol-1-yl-pyridine-3-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluoro-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-3-methoxy-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-3-morpholin-4-yl-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-2-methoxy-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-ethoxyethoxy)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(1-piperidyl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-piperidylmethoxy)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-piperazin-1-yl-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-6-piperazin-1-yl-pyridine-3-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(dimethylaminomethyl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-hydroxyethoxy)benzamide,-   4-(2-aminopropyl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3,3-dimethyl-1-piperidyl)methyl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[4-(2-hydroxyethyl)piperazin-1-yl]benzamide,-   4-[(7-cyano-3,4-dihydro-1H-isoquinolin-2-yl)methyl]-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3-fluoro-1-piperidyl)methyl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-morpholin-4-ylethoxy)benzamide,-   4-[2-(4,4-difluoro-1-piperidyl)ethoxy]-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-morpholin-4-ylethyl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(methyl-(oxolan-2-ylmethyl)amino)methyl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-piperidyl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-dimethylamino-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-5-piperazin-1-yl-thiophene-2-carboxamide,-   methyl    6-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-3-carboxylate,-   6-chloro-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,-   6-cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide,-   4-hydroxy-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-2-carboxamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-(2-pyrrolidin-1-ylethyl)pyridine-3-carboxamide,-   5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylic    acid,-   methyl    5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylate,-   ethyl    5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylate,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)pyridine-2-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(2-dimethylaminoethylamino)benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-methoxy-benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-6-piperazin-1-yl-pyridine-3-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-1H-pyrazol-3-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-1H-pyrazol-3-yl]-3-piperazin-1-yl-benzamide,-   4-(1,4-diazepan-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-1H-pyrazol-3-yl]benzamide,-   N-[5-[2-[5-(dimethylaminomethyl)-2-furyl]ethyl]-1H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-(2-benzo[1,3]dioxol-5-ylethyl)-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[2-(2,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[2-(4-methoxy-2-methyl-phenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-iodo-benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-2-[(3-methyl-1,2-oxazol-5-yl)methylamino]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-methylpiperazine-1-carbonyl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-propan-2-ylpiperazin-1-yl)benzamide,-   4-(4-cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide,-   4-(4-cyclobutylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide,-   4-(4-acetylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3-methoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-methylsulfonylpiperazin-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(1-methyl-4-piperidyl)benzamide,-   4-(3,4,6,7,8,8a-Hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   4-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4,5-trimethylpiperazin-1-yl)benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxamide,-   4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide,-   4-(1-Cyclopropylpiperidin-4-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide,-   tert-Butyl    4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(1-methylpiperidin-4-yl)benzamide,-   4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide,-   5-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)thiophene-2-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)thiophene-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3,3-dimethylpiperazin-1-yl)pyrazine-2-carboxamide,-   5-(4-Cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-[(3R,5    S)-3,5-dimethylpiperazin-1-yl]pyrazine-2-carboxamide,-   5-(4-Cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   5-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   5-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   4-(4-cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-4-oxidopiperazin-4-ium-1-yl)benzamide,-   4-(4-Cyclobutylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide,-   2-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide,-   5-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]thiophene-2-carboxamide,-   5-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]thiophene-2-carboxamide,-   5-(3,4,6,7,8,8a-Hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3,4-dimethylpiperazin-1-yl)pyrazine-2-carboxamide,-   N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(3,4-dimethylpiperazin-1-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-[(3R,5    S)-3,4,5-trimethylpiperazin-1-yl]pyrazine-2-carboxamide,-   2-(4-cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide,-   2-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide,-   2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide,-   5-[(3R,5S)-4-(cyanomethyl)-3,5-dimethylpiperazin-1-yl]-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrazine-2-carboxamide,-   5-[(3R,5S)-4-(cyanomethyl)-3,5-dimethylpiperazin-1-yl]-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide,-   2-(4-cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide,-   2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-[(3R,5    S)-3,4,5-trimethylpiperazin-1-yl]pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[4-(1-hydroxypropan-2-yl)piperazin-1-yl]benzamide,-   N-(3-(3,5-dimethoxybenzyloxy)-1H-pyrazol-5-yl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-ethylpiperazin-1-yl)thiophene-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-ethyl-3-methylpiperazin-1-yl)pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-enylpiperidin-4-yl)benzamide,-   4-(1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-ynylpiperidin-4-yl)benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-[(3S,5R)-3,5-dimethylpiperazin-1-yl]thiophene-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[1-(2-methoxyethyl)piperidin-4-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-[(3    S)-3-propan-2-ylpiperazin-1-yl]pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxamide,-   4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(1-methylpiperidin-4-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5    S)-3,4,5-trimethylpiperazin-1-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3-dimethylaminopyrrolidin-1-yl)pyrazine-2-carboxamide,-   5-(3-diethylaminopyrrolidin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-ethylpiperidin-4-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-[3-(methoxymethyl)piperazin-1-yl]pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3-methylaminopyrrolidin-1-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-methyl-1,4-diazepan-1-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-prop-2-enyl-1,4-diazepan-1-yl)benzamide,-   4-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-yl-1,4-diazepan-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-propan-2-yl-1,4-diazepan-1-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-ethyl-1,4-diazepan-1-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-ethyl-1,4-diazepan-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-prop-2-enyl-1,4-diazepan-1-yl)pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide,-   5-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-prop-2-enyl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide,-   2-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide,-   N-[5-[2-[3-(methylcarbamoyl)phenyl]ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide,-   N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(4-ethylpiperazin-1-yl)benzamide,-   N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-ethylpiperazin-1-yl)benzamide    and pharmaceutically acceptable salts of any one thereof.

In another aspect of the invention, particular compounds of theinvention are any one of the Examples 1 to 20 or pharmaceuticallyacceptable salts of any one thereof.

In another aspect of the invention, particular compounds of theinvention are any one of the Examples or pharmaceutically acceptablesalts of any one thereof.

In another aspect of the invention, particular compounds of theinvention are any one of Examples 1, 2, 3, 4, 5, 10, 11, 12, 20, 42, 43,44, 45, 46, 47, 48, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 69, 70, 71,72, 73, 74, 75, 80, 81, 85, 87, 88, 89, 92, 93, 94, 95, or 96, orpharmaceutically acceptable salts of any one thereof.

In another aspect of the invention, particular compounds of theinvention are any one of Examples 2, 3, 4, 5, 10, 11, 12, 20, 42, 43,44, 45, 46, 47, 48, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 69, 70, 71,72, 73, 74, 75, 80, 81, 85, 87, 88, 89, 92, 93, 94, 95, or 96, orpharmaceutically acceptable salts of any one thereof.

In another aspect of the invention, particular compounds of theinvention are any one of Examples 10, 11, 12, 20, 43, 44, 45, 46, 50,51, 53, 54, 55, 56, 57, 58, 59, 60, 69, 70, 72, 73, 74, 75, 80, 81, 85,87, 88, 89, 92, 93, 94, 95, or 96, or pharmaceutically acceptable saltsof any one thereof.

In another aspect of the invention, particular compounds of theinvention are any one of Examples 2, 3, 4, 10, 11, 12, 20, 42, 43, 45,47, 50, 56, 57, 59, 60, 69, 70, 71, 73, 75, 80, 81, 85, 87, 88, 89, 92,93, 94, 96, 97, 98, 99, 100, 101, 103, 104, 105, 106, 107, 108, 109,110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124,125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138,139, 140, 141, 142, 144, 145, 146, 147, 148, 151, 152, 153, 154, 155,156, 157, 158, 159, 161, 165, 166, 167, 168, 169, 170, 171, 172, 174,175, 176, 177, 179 or 180, or pharmaceutically acceptable salts of anyone thereof.

In another aspect of the invention, particular compounds of theinvention are any one of Examples 12, 45, 73, 75, 81, 92, 98, 99, 100,103, 104, 110, 121, 137, 144, 148, 152, 154, 155, 159, 167, 179 or 180,or pharmaceutically acceptable salts of any one thereof.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined herein, or a pharmaceuticallyacceptable salt thereof, which comprises reacting a compound of formula(II)

-   -   wherein Z represents a leaving group (e.g. halogen, for example        chlorine, —CN, —N₃, —OH or a —OR, —OC(O)R, —OCR(NR^(a)R^(b))₂ or        —OC(═NR)NR^(a)R^(b) group where R is an optionally substituted        alkyl, aryl, heteroaryl or alkaryl and each R^(a), R^(b)        independently is hydrogen or an optionally substituted alkyl,        aryl or alkaryl), and B, R² and b are as hereinbefore defined        for a compound formula (I),        with a compound of formula (III)

-   -   wherein Q is hydrogen or a protecting group (for example t-Bu or        BOC group or as described in ‘Protective Groups in Organic        Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts,        Wiley-Interscience (1991)), and A, R¹, R³, X, Y and a are as        defined hereinbefore for a compound of formula (I)        to give a compound of formula (I),        and optionally carrying out one or more of the following:    -   converting the compound obtained to a further compound of the        invention    -   forming a pharmaceutically acceptable salt of the compound.

Suitable compounds of Formula (II) include carboxylic acids or reactivederivatives of a carboxylic acid. Carboxylic acids or reactivederivatives of a carboxylic acid include acyl halides, such as an acylchloride formed by the reaction of the acid with an inorganic acidchloride, for example thionyl chloride; a mixed anhydride, for examplean anhydride formed by the reaction of the acid with a chloroformatesuch as isobutyl chloroformate; an active ester, for example an esterformed by the reaction of a carboxylic acid with a phenol such aspentafluorophenol, with an ester, such as pentafluorophenyltrifluoroacetate, or with an alcohol such as methanol, ethanol,isopropanol, butanol or N-hydroxybenzotriazole; an acyl azide, forexample an azide formed by the reaction of the acid with an azide suchas diphenylphosphoryl azide; an acyl cyanide, for example a cyanideformed by the reaction of an acid with a cyanide such asdiethylphosphoryl cyanide; or the product of the reaction of the acidwith a carbodiimide such as dicyclohexylcarbodiimide or with a uroniumcompound such as 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V).

The reaction may conveniently be carried out in the presence of asuitable inert solvent or diluent, for example a halogenated solventsuch as methylene chloride, chloroform or carbon tetrachloride, analcohol or ester such as methanol, ethanol, isopropanol or ethylacetate, an ether such as tetrahydrofuran or 1,4-dioxan, an aromaticsolvent such as toluene. The reaction can also be carried out in thepresence of a dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.The reaction is conveniently carried out at a temperature in the range,for example, −20° C. to 100° C., preferably between 0° C. to ambienttemperature, dependant upon the reaction being carried out and thenature of the leaving group Z.

The reaction typically can be carried out in the presence of a base.Suitable bases include organic amine bases, such as pyridine,2,6-lutidine, N,N-diisopropylethylamine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, alkali or alkaline earth metalcarbonates or hydroxides, such as sodium carbonate, potassium carbonate,calcium carbonate, sodium hydroxide or potassium hydroxide, alkali metalamides, such as sodium hexamethyldisilazide (NaHMDS), or alkali metalhydrides, such as sodium hydride, dependant upon the reaction beingcarried out and the nature of the leaving group Z.

The reaction can also be carried out in the presence of a Lewis acid,for example trimethylaluminium, dependant upon the reaction beingcarried out and the nature of the leaving group Z.

Alternatively, the present invention further provides a process for thepreparation of a compound of formula (I) as defined herein, or apharmaceutically acceptable salt thereof, which comprises reacting acompound of formula (IV)

-   -   wherein Q is hydrogen or a protecting group (for example t-Bu or        BOC group or as described in ‘Protective Groups in Organic        Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts,        Wiley-Interscience (1991)); and B, R², R³ and b are as defined        hereinbefore for a compound of formula (I),        with a compound of formula (V)

-   -   wherein L¹ represents OH or a leaving group such as halogen or        OTs; and A, R¹ and a are as defined hereinbefore for a compound        of formula (I)        to give a compound of formula (I)        and optionally carrying out one or more of the following:    -   converting the compound obtained to a further compound of the        invention    -   forming a pharmaceutically acceptable salt of the compound.

The reaction may conveniently be carried out in a suitable solvent suchas dichloromethane at temperature in the range from 0° C. to roomtemperature. When L¹ is OH, the reaction typically may be carried out inthe presence of diisopropylazidocarboxylate and triphenylphosphine. WhenL¹ is a halogen or OTs, the reaction may conveniently be carried out ina suitable solvent such as N,N-dimethylformamide or acetonitrile attemperature in the range from room temperature to 100° C. The reactiontypically may be carried out in the presence of an inorganic base suchas potassium carbonate or sodium hydride.

Compounds of formula (II), (III), (IV) or (V) are either commerciallyavailable, are known in the literature or may be prepared using knowntechniques.

Compounds of formula (II), wherein Z is halogen or —OR, may be preparedfrom compounds of formula (II) wherein Z is —OH by methods known in theliterature. For example, methods known for the preparation of acidchlorides or esters from carboxylic acids may be employed.

Compounds of formula (III) where X represents CH₂ may be prepared byreacting a compound of formula (VI)

with a hydrazine of formula (VII)

The reaction may be conveniently carried out in a solvent, such asethanol, at temperature range of 60 to 80° C.

Alternatively, compounds of formula (III) where X represents O may beprepared by reacting a compound of formula (VIII)

with a compound of formula (IX)

The reaction may be conveniently carried out in a solvent, such asdichloromethane, at temperature range of 0° C. to room temperature. Thereaction typically may be carried out in the presence ofdiisopropylazidocarboxylate and triphenylphosphine.

Compounds of formulae (IV) may be prepared by reacting a compound offormula (X)

with a compound of formula (II)

-   -   wherein Z represents a leaving group (e.g. halogen, for example        chlorine, —CN, —N₃, —OH or a —OR, —OC(O)R, —OCR(NR^(a)R^(b))₂ or        —OC(═NR)NR^(a)R^(b) group where R is an optionally substituted        alkyl, aryl, heteroaryl or alkaryl and each R^(a), R^(b)        independently is hydrogen or an optionally substituted alkyl,        aryl or alkaryl);        -   P represents H or a protecting group (for example as            described in ‘Protective Groups in Organic Synthesis’, 2nd            edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience            (1991));        -   Q is hydrogen or a protecting group (for example t-Bu or BOC            group or as described in ‘Protective Groups in Organic            Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts,            Wiley-Interscience (1991)); and        -   B, R², R³ and b and wherein are as defined hereinbefore for            a compound of formula (I),            and, when P is a protecting group, removing protecting group            P.

Compounds of formula (VI), (VII), (VIII) and (IX) are commerciallyavailable compounds, or they are known in the literature, or they areprepared by standard processes known in the art.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures. Examples of the types ofconversion reactions that may be used include introduction of asubstituent by means of an aromatic substitution reaction, reduction ofsubstituents, alkylation of substituents and oxidation of substituents.The reagents and reaction conditions for such procedures are well knownin the chemical art. Examples of aromatic substitution reactions includethe introduction of a nitro group using concentrated nitric acid; theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an aryl group, for example, using anaryl halide under Suzuki conditions; the introduction of an amino groupusing, for example, an aryl halide and an amine under Buchwaldconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogen group. Examples ofreduction reactions include the reduction of a nitro group to an aminogroup by catalytic hydrogenation with a nickel catalyst or by treatmentwith iron in the presence of hydrochloric acid with heating; andparticular examples of oxidation reactions include oxidation ofalkylthio to alkylsulphinyl or alkylsulphonyl. These reagents andreaction conditions described above are well known in the art.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at various stages, the additionand removal of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt, for example an acid addition salt suchas a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, oran alkali metal salt such as a sodium or potassium salt.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses the use of all geometric and optical isomers (includingatropisomers) of the compounds of formula (I) and mixtures thereofincluding racemates. The use of tautomers and mixtures thereof also forman aspect of the present invention.

Certain compounds of formula (I), a pharmaceutically acceptable saltthereof, may be isolated as an amorphous solid or as a crystallinesolid. If the compound is in crystalline form, it may exist in a numberof different polymorphic forms. Examples of compounds that have beenisolated as either amorphous or crystalline solids include: Example 10isolated as a crystalline form (2-Theta° 3.521 (100%), 7.025 (14.8%),9.274 (16.9%), 9.654 (15.2%), 10.162 (14.8%), 10.508 (19.3%), 11.628(49.8%), 12.047 (19.3%), 14.516 (21%), 16.242 (26.3%), 17.682 (18.5%),18.099 (31.3%), 18.615 (92.6%), 19.315 (56.8%), 20.353 (16%), 20.581(17.3%), 21.192 (10.3%), 22.467 (23%), 23.057 (88.1%), 23.28 (52.3%),24.261 (34.2%), 25.363 (10.7%), 27.546 (15.6%), 28.285 (14%) and 29.862(11.9%); Example 75 isolated as an amorphous solid; Example 81 isolatedas an amorphous solid; Example 144 isolated as a crystalline form(2-Theta° 3.62 (100%), 7.247 (4.6%), 10.013 (5.1%), 10.889 (8.1%),11.294 (7.7%), 12.185 (8.6%), 14.091 (19%), 18.2 (12.7%), 19.102 (8.9%),19.789 (15.2%) and 20.608 (32.7%); Example 99 isolated as a crystallineform (2-Theta° 4.293 (100%), 8.498 (14%), 10.694 (8.1%), 13.078 (4.5%),15.056 (49.4%), 16.14 (8.1%), 16.298 (11.1%), 17.425 (34.6%), 17.812(23.1%), 18.157 (9.6%), 19.224 (15%), 20.931 (20.2%), 21.819 (27.9%),22.248 (16.2%), 22.593 (23.7%), 23.416 (8.8%), 24.726 (26%), 25.295(11.6%), 25.859 (5.6%), 27.001 (5.9%), 27.754 (5.3%), 28.442 (4.8%),29.861 (4.3%), 30.89 (3.8%), 32.264 (5.9%) and 32.896 (5.4%); Example147 isolated as a crystalline form (2-Theta° 4.492 (91.3%), 12.465(23.1%), 13.862 (26.3%), 14.56 (14.4%), 15.811 (16.3%), 17.226 (24.4%),17.886 (20%), 18.3 (15%), 18.9 (100%), 21.328 (20%), 21.705 (28.1%),23.263 (27.5%), 23.699 (19.4%), 24.005 (53.8%), 24.333 (37.5%), 25.184(11.9%), 26.114 (11.3%), 26.573 (10.6%) and 27.803 (16.9%); Example 151isolated as a crystalline form (2-Theta° 3.754 (29.6%), 8.495 (13.9%),10.235 (19.1%), 10.98 (29.6%), 12.014 (23.5%), 13.38 (18.3%), 14.591(33%), 15.924 (41.7%), 17.057 (26.1%), 17.379 (30.4%), 18.219 (32.2%),18.791 (36.5%), 19.201 (100%), 19.577 (47.8%), 20.788 (33%), 21.394(27%), 22.07 (33%), 23.285 (25.2%), 23.922 (29.6%) and 25.533 (33%);Example 154 isolated as a crystalline form (2-Theta° 5.833 (89.6%),9.786 (21.9%), 10.784 (32.8%), 12.121 (30.7%), 13.394 (35.4%), 13.709(45.3%), 14.939 (28.1%), 16.799 (35.4%), 17.664 (25%), 18.223 (21.9%),18.646 (50%), 19.29 (25.5%), 20.563 (35.4%), 21.32 (100%), 22.747(37.5%), 24.154 (38.5%), 25.197 (23.4%), 25.704 (15.1%), 26.752 (16.7%)and 31.134 (12%); and Example 155 isolated as an amorphous solid. Unlessotherwise stated, the X-ray powder diffraction patterns were determinedby mounting a sample of the crystalline material on Siemens singlesilicon crystal (SSC) wafer mounts and spreading out the sample into athin layer with the aid of a microscope slide. The sample was spun at 30revolutions per minute (to improve counting statistics) and irradiatedwith X-rays generated by a copper long-fine focus tube operated at 40 kVand 40 mA with a wavelength of 1.5418 Angstroms using a SiemensDiffraktometer 5000. The collimated X-ray source was passed through anautomatic variable divergence slit set at V20 and the reflectedradiation directed through a 2 mm antiscatter slit and a 0.2 mm detectorslit. The sample was exposed for 1 second per 0.02 degree 2-thetaincrement (continuous scan mode) over the range 2 degrees to 40 degrees2-theta in theta-theta mode. The instrument was equipped with ascintillation counter as detector. Control and data capture was by meansof a Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac+software.

A person skilled in the art will appreciate that the diffraction patterndata presented herein is not to be construed as absolute (for furtherinformation see Jenkins, R & Snyder, R. L. ‘Introduction to X-Ray PowderDiffractometry’ John Wiley & Sons, 1996). Therefore, it shall beunderstood that the crystalline form is not intended to be limited tothe crystals that provide X-ray powder diffraction patterns identical tothe X-ray powder diffraction patterns described herein. The presentinvention also includes any crystals providing X-ray powder diffractionpatterns substantially the same as those described herein. A personskilled in the art of X-ray powder diffraction is able to judge thesubstantial similarity of X-ray powder diffraction patterns and willunderstand that differences may be the result of various factors forexample measurement errors resulting from measurement conditions (suchas equipment, sample preparation or the machine used); intensityvariations resulting from measurement conditions and sample preparation;relative intensity variations of peaks resulting from variations in sizeor non-unitary aspect ratios of crystals; and the position ofreflections which can be affected by the precise height at which thesample sits in the diffractometer and the zero calibration of thediffractometer, and surface planarity of the sample.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators or inhibitors of FGFR activity, and may be usedin the treatment of proliferative and hyperproliferativediseases/conditions, examples of which include the following cancers:

(1) carcinoma, including that of the bladder, brain, breast, colon,kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon,thyroid and skin;

(2) hematopoietic tumors of lymphoid lineage, including acutelymphocytic leukaemia, B-cell lymphoma and Burketts lymphoma;

(3) hematopoietic tumours of myeloid lineage, including acute andchronic myelogenous leukaemias and promyelocytic leukaemia;

(4) tumours of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma; and

(5) other tumours, including melanoma, seminoma, teratocarcinoma,neuroblastoma and glioma.

In one embodiment the compounds of the invention are useful in thetreatment of tumors of the bladder, breast and prostate and multiplemyeloma.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt thereof, as herein defined for use intherapy.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt, asherein defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides a method of treating cancer which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as herein defined.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt thereof, are effective anti-canceragents which property is believed to arise from modulating or inhibitingFGFR activity. Accordingly the compounds of the present invention areexpected to be useful in the treatment of diseases or medical conditionsmediated alone or in part by FGFR, i.e. the compounds may be used toproduce a FGFR inhibitory effect in a warm-blooded animal in need ofsuch treatment.

Thus the compounds of the present invention provide a method fortreating cancer characterised by inhibition of FGFR, i.e. the compoundsmay be used to produce an anti-cancer effect mediated alone or in partby the inhibition of FGFR.

Such a compound of the invention is expected to possess a wide range ofanti-cancer properties as activating mutations in FGFR have beenobserved in many human cancers, including but not limited to breast,bladder, prostrate and multiple myeloma. Thus it is expected that acompound of the invention will possess anti-cancer activity againstthese cancers. It is in addition expected that a compound of the presentinvention will possess activity against a range of leukaemias, lymphoidmalignancies and solid tumours such as carcinomas and sarcomas intissues such as the liver, kidney, bladder, prostate, breast andpancreas. In one embodiment compounds of the invention are expected toslow advantageously the growth of primary and recurrent solid tumoursof, for example, the skin, colon, thyroid, lungs and ovaries. Moreparticularly such compounds of the invention, or a pharmaceuticallyacceptable salt thereof, are expected to inhibit the growth of thosetumours which are associated with FGFR, especially those tumours whichare significantly dependent on FGFR for their growth and spread,including for example, certain tumours of the bladder, prostrate, breastand multiple myeloma.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined herein for use as a medicament.

According to a further aspect of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe production of a FGFR inhibitory effect in a warm-blooded animal suchas man.

According to this aspect of the invention there is provided the use of acompound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe production of an anti-cancer effect in a warm-blooded animal such asman.

According to a further feature of the invention, there is provided theuse of a compound of the formula (I), or a pharmaceutically acceptablesalt thereof, as defined herein in the manufacture of a medicament foruse in the treatment of melanoma, papillary thyroid tumours,cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer,leukaemias, lymphoid malignancies, multiple myeloma, carcinomas andsarcomas in the liver, kidney, bladder, prostate, breast and pancreas,and primary and recurrent solid tumours of the skin, colon, thyroid,lungs and ovaries.

According to a further aspect of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the production of a FGFR inhibitory effectin a warm-blooded animal such as man.

According to this aspect of the invention there is provided the use of acompound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the production of an anti-cancer effect ina warm-blooded animal such as man.

According to a further feature of the invention, there is provided theuse of a compound of the formula (I), or a pharmaceutically acceptablesalt thereof, as defined herein in the treatment of melanoma, papillarythyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lungcancer, leukaemias, lymphoid malignancies, multiple myeloma, carcinomasand sarcomas in the liver, kidney, bladder, prostate, breast andpancreas, and primary and recurrent solid tumours of the skin, colon,thyroid, lungs and ovaries.

According to a further feature of this aspect of the invention there isprovided a method for producing a FGFR inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, asdefined herein.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-cancer effect in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof, as definedherein.

According to an additional feature of this aspect of the invention thereis provided a method of treating melanoma, papillary thyroid tumours,cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer,leukaemias, lymphoid malignancies, multiple myeloma, carcinomas andsarcomas in the liver, kidney, bladder, prostate, breast and pancreas,and primary and recurrent solid tumours of the skin, colon, thyroid,lungs and ovaries, in a warm-blooded animal, such as man, in need ofsuch treatment which comprises administering to said animal an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof as defined herein.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined herein inassociation with a pharmaceutically-acceptable diluent or carrier foruse in the production of a FGFR inhibitory effect in a warm-bloodedanimal such as man.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined herein inassociation with a pharmaceutically-acceptable diluent or carrier foruse in the production of an anti-cancer effect in a warm-blooded animalsuch as man.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined herein inassociation with a pharmaceutically-acceptable diluent or carrier foruse in the treatment of melanoma, papillary thyroid tumours,cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer,leukaemias, lymphoid malignancies, multiple myeloma, carcinomas andsarcomas in the liver, kidney, bladder, prostate, breast and pancreas,and primary and recurrent solid tumours of the skin, colon, thyroid,lungs and ovaries in a warm-blooded animal such as man.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound or salt (active ingredient) is in association with apharmaceutically acceptable adjuvant, diluent or carrier. Depending onthe mode of administration, the pharmaceutical composition may comprisefrom 0.01 to 99% w (percent by weight), from 0.05 to 80% w, from 0.10 to70% w, and or even from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as herein defined, in association with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,as herein defined, with a pharmaceutically acceptable adjuvant, diluentor carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of solutions or suspensions; or bysubcutaneous administration; or by rectal administration in the form ofsuppositories; or transdermally.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30μ or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium chromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The size of the dose for therapeutic purposes of a compound of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well known principles of medicine.

In general, a compound of the invention will be administered so that adaily dose in the range, for example, from 0.1 mg to 1000 mg activeingredient per kg body weight is received, given if required in divideddoses. However the daily dose will necessarily be varied depending uponthe host treated, the particular route of administration, and theseverity of the illness being treated. Accordingly the optimum dosagemay be determined by the practitioner who is treating any particularpatient. In general lower doses will be administered when a parenteralroute is employed. Thus, for example, for intravenous administration, adose in the range, for example, from 0.1 mg to 30 mg active ingredientper kg body weight will generally be used. Similarly, for administrationby inhalation, a dose in the range, for example, from 0.1 mg to 25 mgactive ingredient per kg body weight will generally be used. Oraladministration is however preferred. For example, a formulation intendedfor oral administration to humans will generally contain, for example,from 0.1 mg to 2 g of active ingredient.

For further information on Routes of Administration and Dosage Regimesthe reader is referred to Chapter 25.3 in Volume 5 of ComprehensiveMedicinal Chemistry (Corwin Hansch; Chairman of Editorial Board),Pergamon Press 1990.

The anti cancer treatment defined hereinbefore may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of

5*-reductase such as finasteride;

(iii) anti-invasion agents (for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341) andN-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), andmetalloproteinase inhibitors like marimastat, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase);

(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI 774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib,inhibitors of the hepatocyte growth factor family, inhibitors of theplatelet-derived growth factor family such as imatinib, inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas famesyl transferase inhibitors, for example sorafenib (BAY 43-9006)),inhibitors of cell signalling through MEK and/or AKT kinases, inhibitorsof the hepatocyte growth factor family, c-kit inhibitors, abl kinaseinhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and VEGFreceptor tyrosine kinase inhibitors such as4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin avb3 function andangiostatin)];

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene directed enzyme pro drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex vivo and in vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte macrophage colony stimulating factor, approaches to decreaseT cell anergy, approaches using transfected immune cells such ascytokine transfected dendritic cells, approaches using cytokinetransfected tumour cell lines and approaches using anti idiotypicantibodies.

EXAMPLES

The invention will now be further described with reference to thefollowing illustrative examples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C.;

(ii) organic solutions were dried over anhydrous magnesium sulphate;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperatureof up to 60° C.;

(iii) chromatography means flash chromatography on silica gel; thinlayer chromatography (TLC) was carried out on silica gel plates;

(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

(v) final products had satisfactory proton nuclear magnetic resonance(NMR) spectra and/or mass spectral data;

(vi) yields are given for illustration only and are not necessarilythose which can be obtained by diligent process development;preparations were repeated if more material was required;

(vii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHz,in DMSO-d₆ unless otherwise indicated;

(viii) chemical symbols have their usual meanings; SI units and symbolsare used;

(ix) solvent ratios are given in volume:volume (v/v) terms; and

(x) mass spectra (MS) data was generated on an LC/MS system where theHPLC component comprised generally either a Agilent 1100 or WatersAlliance HT (2790 & 2795) equipment and was run on a Phemonenex GeminiC18 5 μm, 50×2 mm column (or similar) eluting with either acidic eluent(for example, using a gradient between 0-95% water/acetonitrile with 5%of a 1% formic acid in 50:50 water:acetonitrile (v/v) mixture; or usingan equivalent solvent system with methanol instead of acetonitrile), orbasic eluent (for example, using a gradient between 0-95%water/acetonitrile with 5% of a 0.1% 880 Ammonia in acetonitrilemixture); and the MS component comprised generally a Waters ZQspectrometer. Chromatograms for Electrospray (ESI) positive and negativeBase Peak Intensity, and UV Total Absorption Chromatogram from 220-300nm, are generated and values for m/z are given; generally, only ionswhich indicate the parent mass are reported and unless otherwise statedthe value quoted is the (M+H)+ for positive ion mode and (M−H)− fornegative ion mode;(xi) Preparative HPLC was performed on C18 reversed-phase silica, forexample on a Waters ‘Xterra’ preparative reversed-phase column (5microns silica, 19 mm diameter, 100 mm length) using decreasingly polarmixtures as eluent, for example decreasingly polar mixtures of water(containing 1% acetic acid or 1% aqueous ammonium hydroxide (d=0.88) andacetonitrile;(xii) the following abbreviations have been used:

-   -   THF tetrahydrofuran;    -   DMF N,N-dimethylformamide;    -   EtOAc ethyl acetate;    -   DCM dichloromethane; and    -   DMSO dimethylsulphoxide    -   DIPEA N,N-diisopropylethylamine (also known as        N-ethyl-N-propan-2-yl-propan-2-amine)    -   PBS phosphate buffered saline    -   HEPES N-[2-Hydroxyethyl]piperazine-N-[2-ethanesulfonic acid]    -   DTT dithiothreitol    -   ATP Adenosine Triphosphate    -   BSA bovine serum albumin    -   DMEM Dulbecco's modified Eagle's Medium    -   MOPS 3-(N-morpholino)propanesulfonic acid        (xiii) compounds are named using proprietary naming software:        Openeye Lexichem version 1.4, using IUPAC naming convention;        (xiv) unless otherwise specified, starting materials are        commercially available.

TABLE 1

Example

X

R³ 1

CH₂

H 2

CH₂

H 3

CH₂

H 4

CH₂

H 5

CH₂

H 6

CH₂

H 7

CH₂

H 8

CH₂

H 9

CH₂

H 10

CH₂

H 11

CH₂

H 12

O

H 13

CH₂

H 14

CH₂

H 15

CH₂

H 16

CH₂

H 17

CH₂

H 18

CH₂

H 19

CH₂

H 20

O

H 21

CH₂

H 22

CH₂

H 23

CH₂

H 24

CH₂

H 25

CH₂

H 26

CH₂

H 27

CH₂

H 28

CH₂

H 29

CH₂

H 30

CH₂

H 31

CH₂

H 32

CH₂

H 33

CH₂

H 34

CH₂

H 35

CH₂

H 36

CH₂

H 37

CH₂

H 38

CH₂

H 39

CH₂

H 40

CH₂

H 41

CH₂

H 42

CH₂

H 43

CH₂

H 44

CH₂

H 45

CH₂

H 46

CH₂

H 47

CH₂

H 48

CH₂

H 49

CH₂

H 50

CH₂

H 51

CH₂

H 52

CH₂

H 53

CH₂

H 54

CH₂

H 55

CH₂

H 56

CH₂

H 57

CH₂

H 58

CH₂

H 59

CH₂

H 60

CH₂

H 61

CH₂

H 62

CH₂

H 63

CH₂

H 64

CH₂

H 65

CH₂

H 66

CH₂

H 67

CH₂

H 68

CH₂

H 69

O

H 70

O

H 71

O

H 72

O

H 73

O

H 74

O

H 75

O

H 76

CH₂

H 77

CH₂

H 78

CH₂

H 79

CH₂

H 80

CH₂

H 81

CH₂

H 82

CH₂

H 83

CH₂

H 84

CH₂

H 85

CH₂

H 86

CH₂

H 87

CH₂

H 88

CH₂

H 89

CH₂

H 90

CH₂

H 91

CH₂

H 92

CH₂

H 93

CH₂

H 94

CH₂

H 95

CH₂

H 96

CH₂

H 97

O

H 98

O

H 99

CH₂

H 100

O

H 101

O

H 102

CH₂

H 103

O

H 104

O

H 105

CH₂

H 106

CH₂

H 107

O

H 108

CH₂

H 109

O

H 110

O

H 111

O

H 112

CH₂

H 113

CH₂

H 114

CH₂

H 115

O

H 116

O

H 117

CH₂

H 118

O

H 119

O

H 120

CH₂

H 121

O

H 122

O

H 123

CH₂

H 124

O

H 125

CH₂

H 126

CH₂

H 127

CH₂

H 128

CH₂

H 129

CH₂

H 130

O

H 131

O

H 132

O

H 133

O

H 134

O

H 135

CH₂

H 136

CH₂

H 137

CH₂

H 138

O

H 139

CH₂

H 140

O

H 141

O

H 142

CH₂

H 143

CH₂

H 144

CH₂

H 145

CH₂

H 146

CH₂

H 147

O

H 148

CH₂

H 149

CH₂

H 150

CH₂

H 151

O

H 152

CH₂

H 153

CH₂

H 154

CH₂

H 155

CH₂

H 156

CH₂

H 157

CH₂

H 158

CH₂

H 159

CH₂

H 160

CH₂

H 161

CH₂

H 162

CH₂

H 163

CH₂

H 164

CH₂

H 165

CH₂

H 166

CH₂

H 167

CH₂

H 168

CH₂

H 169

CH₂

H 170

CH₂

H 171

CH₂

H 172

CH₂

H 173

CH₂

H 174

CH₂

H 175

CH₂

H 176

CH₂

H 177

CH₂

H 178

CH₂

H 179

O

H 180

CH₂

H

Example 14-(4-methylpiperazin-1-yl)-N-(5-phenethyl-2H-pyrazol-3-yl)benzamide

Oxalyl chloride (2M in DCM, 250 μl, 0.50 mmol, 1.1 eq) was addeddropwise to a mixture of 4-(4-methylpiperazin-1-yl)benzoic acid (100 mg,0.45 mmol, 1 eq) in DCM (5 ml, containing a few drops of DMF) and DIPEA(171 μl, 0.95 mmol, 2.1 eq) at 0° C. After stirring for 1 h at 0° C., asolution of 5-phenethyl-2H-pyrazol-3-amine (128 mg, 0.68 mmol, 1.5 eq)in DCM (2 ml) was added dropwise. The mixture was maintained at 0° C.for 2 h, then gradually allowed to warm to room temperature overnight.The mixture was diluted with DCM (50 ml), washed with aq. NaHCO₃solution (50 ml) and the aqueous layer was extracted with DCM (50 ml).The combined organic layers were concentrated. The crude product waspurified by reverse-phase prep. HPLC (basic) using a 30-50% gradient ofacetonitrile in water (containing 1% ammonium hydroxide) to yield thetitle compound (8 mg, 3% yield).

¹H NMR (300.132 MHz, DMSO) δ 2.23 (3H, s), 2.44 (4H, t), 2.84-2.95 (4H,m), 3.26-3.30 (4H, m), 6.41 (1H, s), 6.96 (2H, d), 7.15-7.33 (5H, m),7.89 (2H, d), 10.30 (1H, s), 12.08 (1H, s). MS m/z 390 (MH+)

FGFR Kinase assay—Elisa, IC₅₀ 0.22 μM.

Example 2 N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

Benzoyl chloride (56 μl, 0.47 mmol, 1.1 eq) was added dropwise to amixture of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (150 mg,0.43 mmol, 1 eq) and pyridine (104 μl, 1.29 mmol, 3 eq) in DCM (1.5 ml)at ambient temperature. After stirring at ambient temperature for 2 h, asolution of TFA (321 μl, 4.32 mmol, 10 eq) in DCM (2.7 ml) was addeddropwise and stirring was continued for a further 1 h. The reactionmixture was concentrated and the crude product was purified byreverse-phase prep. HPLC (basic) using a 33-53% gradient of acetonitrilein water containing 1% ammonium hydroxide solution. The clean fractionswere taken and evaporated to afford the title compound as a colourlessfoamy solid (100 mg, 66% yield).

¹H NMR (399.902 MHz, DMSO) δ 2.81 (4H, s), 3.65 (6H, s), 6.26-6.25 (1H,m), 6.35 (2H, d), 6.41 (1H, s), 7.50-7.39 (3H, m), 7.91 (2H, d), 10.56(1H, s), 12.07 (1H, s). MS: m/z 352 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.140 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate, used asstarting material was prepared as follows:

A solution of di-tert-butyl dicarbonate (464 mg, 2.12 mmol, 1.05 eq) inDCM (2 ml) was added dropwise to a mixture of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (500 mg, 2.02 mmol,1 eq) in DCM (18 ml) containing aq. KOH solution (4.5 N, 3.6 ml, ca. 16mmol, 8 eq). The reaction mixture was transferred to a separating funneland the layers separated. The organic layer was washed with water (10ml), brine (10 ml) and dried over sodium sulfate. After filtering thesolvent was evaporated under reduced pressure to yield a pale yellow oilwhich solidified on standing overnight to afford a cream solid (704 mg,100% yield).

¹H NMR (399.902 MHz, DMSO) δ 1.56 (9H, s), 2.68-2.63 (2H, m), 2.80-2.75(2H, m), 3.73 (6H, s), 5.22 (1H, s), 6.23 (2H, br.s), 6.32-6.31 (1H, m),6.44 (2H, d). MS: m/z 370 ([M+Na]+).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as follows:

Acetonitrile (2.29 ml, 43.61 mmol, 1.2 eq) was added to a slurry ofsodium hydride (1.75 g dispersion in mineral oil, 43.61 mmol, 1.2 eq) inanhydrous toluene (70 ml) and the mixture stirred at room temperaturefor 30 mins. Ethyl 3-(3,5-dimethoxyphenyl)propanoate (8.66 g, 36.34mmol, 1 eq) in toluene (60 ml) was added and the reaction was refluxedfor 18 h. After cooling, the reaction mixture was quenched with waterand the solvent was evaporated under reduced pressure. The residue wasdissolved in 2M HCl (50 ml). The acidic solution was extracted withethyl acetate. The organic extracts were combined and washed with water,brine and dried over magnesium sulphate. After filtering, the solventwas evaporated under reduced pressure to yield the crude product as ayellow oil. The oil was purified by silica column chromatography(eluting with DCM) and the desired fractions were combined andevaporated to yield a cream solid (3.76 g, 44% yield).

To the cream solid (3.72 g, 15.96 mmol, 1 eq) in ethanol (55 ml) wasadded hydrazine hydrate (852 μl, 17.56 mmol, 1.1 eq). The reaction wasrefluxed for 24 h before allowing to cool. After evaporation underreduced pressure, the residue was extracted into DCM. The organic layerswere washed with water, brine, dried with magnesium sulphate, filteredand evaporated under reduced pressure to afford5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine as a pale yellowsolid (3.76 g. 42% over 2 steps).

¹H NMR (300.132 MHz, DMSO) δ 2.64-2.82 (4H, m), 3.71 (6H, s), 4.07-4.72(2H, m), 5.20 (1H, s), 6.31 (1H, t), 6.38 (2H, d). MS: m/z 248 (MH+)

Example 3N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-methoxy-benzamide

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (89 μl, 0.63 mmol, 1.05 eq)was added dropwise to 4-methoxybenzoic acid (97 mg, 0.63 mmol, 1 eq) inDCM (1.5 ml) at ambient temperature. After stirring at ambienttemperature for 1.5 h, a solution of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (199 mg,0.57 mmol, 0.9 eq) and pyridine (142 μL, 1.74 mmol, 2.75 eq) in DCM (2ml) was added to the reaction mixture and stirring was continued atambient temperature for a further 3 h. A solution of TFA (386 μL, 5.2mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continuedat ambient temperature for 18 h. The reaction mixture was concentratedand the crude product was purified by reverse-phase prep. HPLC (basic)using a 33-53% gradient of acetonitrile in water containing 1% ammoniumhydroxide solution. The clean fractions were taken and evaporated toafford the title compound as a colourless foamy solid (113 mg, 52%yield).

¹H NMR (399.902 MHz, DMSO) δ 2.88 (4H, s), 3.73 (6H, s), 3.84 (3H, s),6.34-6.32 (1H, m), 6.42 (2H, d), 6.47 (1H, s), 7.01 (2H, d), 7.99 (2H,d), 10.48 (1H, br.s), 12.12 (1H, br.s).

MS: m/z 382 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.132 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate, used asstarting material was prepared as in Example 2.

Example 4N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-morpholin-4-yl-benzamide

Prepared in an analogous way to Example 3 to give the title compound asa solid (125 mg, 50% yield).

¹H NMR (399.902 MHz, DMSO) δ 2.88 (4H, s), 3.26-3.24 (4H, m), 3.76-3.72(10H, m), 6.34-6.32 (1H, m), 6.46-6.42 (3H, m), 6.98 (2H, d), 7.92 (2H,d), 10.35 (1H, br.s), 12.10 (1H, br.s).

MS: m/z 437 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.068 μM.

Example 5N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(4-fluoropiperidin-1-yl)methyl]benzamide

A solution of NaHMDS in THF (1 M, 0.65 ml, 0.65 mmol, 1.5 eq) was addeddropwise at ambient temperature to a mixture of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl) ethyl]pyrazole-1-carboxylate (150 mg,0.43 mmol, 1 eq) and methyl 4-[(4-fluoropiperidin-1-yl)methyl]benzoate(131 mg, 0.52 mmol, 1.2 eq) in THF (0.5 ml). The reaction mixture wasstirred at ambient temperature for 1 h. It was then concentrated and thecrude product was purified by reverse-phase prep. HPLC (basic) using a39-49% gradient of acetonitrile in water containing 1% ammoniumhydroxide solution. The clean fractions were taken and evaporated toafford the title compound as a colourless solid (33 mg, 16% yield).

¹H NMR (399.902 MHz, DMSO) δ 1.78-1.67 (2H, m), 1.94-1.80 (2H, m),2.35-2.29 (2H, m), 2.57-2.55 (2H, m), 2.89 (4H, s), 3.55 (2H, s), 3.73(6H, s), 4.79-4.61 (1H, m), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.48 (1H,s), 7.40 (2H, d), 7.95 (2H, d), 10.59 (1H, br.s), 12.15 (1H, br.s).

MS: m/z 467 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.063 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate, used asstarting material was prepared as in Example 2.

Methyl 4-[(4-fluoropiperidin-1-yl)methyl]benzoate, used as startingmaterial was prepared as follows:

4-Fluoropiperidine hydrochloride (366 mg, 2.62 mmol, 1.2 eq) was addedin one portion to a mixture of methyl 4-(bromomethyl)benzoate (500 mg,2.18 mmol, 1 eq) and MP-carbonate (2.74 mmol/g, 1.912 g, 5.24 mmol, 2.4eq) in MeCN (10 ml). The reaction mixture was stirred at ambienttemperature for 18 h. Polymer-supported isocyanate (1 mmol/g, 500 mg,0.5 mmol, 0.5 eq) was added in one portion and stirring continued for 4h. The reaction mixture was filtered, the resins washed with MeCN andthe combined filtrate was concentrated to afford a clear oil, 478 mg,87% yield at 80% purity.

¹H NMR (399.902 MHz, CDCl3) δ 1.98-1.83 (4H, m), 2.40-2.34 (2H, m),2.61-2.54 (2H, m), 3.55 (2H, s), 3.91 (3H, s), 4.77-4.60 (1H, m), 7.40(2H, d), 8.00-7.98 (2H, m). MS: m/z 252 (MH+).

Example 6N-[5-[2-[3-(2-methoxyethoxy)phenyl]ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

To 4-(4-methylpiperazin-1-yl)benzoic acid (440 mg, 2 mmol, 1 eq) indichloromethane (10 ml) at 0° C. was added a few drops ofN,N-dimethylformamide followed by the dropwise addition of a 2M solutionof oxalyl chloride in dichloromethane (1.1 ml, 2.2 mmol, 1.1 eq). Thereaction was maintained at 0° C. for 1 h.5-[2-[3-(2-Methoxyethoxy)phenyl]ethyl]-2H-pyrazol-3-amine (628 mg, 2.4mmol, 1.2 eq) in dichloromethane (10 ml) was then added dropwisefollowed by DIPEA (750 μl, 4.20 mmol, 2.1 eq). The reaction wasmaintained at 0° C. for a further hour before allowing to warm to roomtemperature overnight. The mixture was diluted with DCM (50 ml) andwashed with aq. NaHCO₃ solution (50 ml). The aqueous layer was extractedwith DCM (50 ml). The organic extracts were combined, washed with brine,dried with magnesium sulphate and evaporated under reduced pressure. Thecrude product was purified by acidic reverse-phase prep. HPLC. Fractionscontaining product were captured onto a SCX-2 column. After washing withmethanol, the crude product was released with 10% ammonia in methanol.After evaporation under reduced pressure, the crude product wasre-purified on the basic reverse-phase prep. HPLC using a 20-45%gradient of acetonitrile in water containing 1% ammonium hydroxide toyield, after evaporation, a white solid (22.9 mg, 2.5%).

¹H NMR (300.132 MHz, DMSO) δ 2.22 (3H, s), 2.44 (4H, t), 2.88 (4H, s),3.27 (4H, t), 3.30 (3H, s), 3.64 (2H, dd), 4.06 (2H, dd), 6.41 (1H, s),6.72-6.84 (3H, m), 6.95 (2H, d), 7.18 (1H, t), 7.88 (2H, d), 10.30 (1H,s), 12.06 (1H, s) MS: m/z 464 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.058 μM.

5-[2-[3-(2-methoxyethoxy)phenyl]ethyl]-2H-pyrazol-3-amine used asstarting material was prepared as follows:

To sodium hydride (1.065 g, 26.57 mmol, 1.1 eq) was added anhydrous1,4-dioxane (40 ml) followed by anhydrous acetonitrile (1.52 ml, 29mmol, 1.2 eq). 2-Methoxyethyl 3-[3-(2-methoxyethoxy)phenyl]propanoate(6.82 g, 24.16 mmol, 1 eq) in anhydrous 1,4-dioxane (35 ml) was thenadded. The reaction was refluxed for 18 h. After cooling, the brownsolution was quenched with water. The solvent was evaporated underreduced pressure and the aqueous residue was acidified with 2M HCl andextracted with ethyl acetate. The organic layers were combined, washedwith 2M HCl, water and brine. After drying (magnesium sulphate), thesolution was filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography eluting with 0-50% ethylacetate in hexanes. The desired intermediate was obtained, afterevaporation, as a yellow oil (3.24 g, 54%). To this intermediate (3.24g, 13.10 mmol, 1 eq) in ethanol (65 ml) was added hydrazine.monohydrate(700 ul, 14.41 mmol, 1.1 eq). The reaction was refluxed at 85° C. for 18h. The solvent was evaporated under reduced pressure. The residue wasextracted with ethyl acetate, washed with water and brine, dried(magnesium sulphate), filtered and evaporated under reduced pressure toyield a yellow oil (2.78 g, 81%).

¹H NMR (300.132 MHz, DMSO) δ 2.68-2.84 (4H, m), 3.31 (3H, s), 3.65 (2H,dd), 4.06 (2H, dd), 4.40 (2H, s), 5.19 (1H, s), 6.71-6.81 (3H, m), 7.17(1H, t), 11.08 (1H, s); MS: m/z 262 (MH+).

2-Methoxyethyl 3-[3-(2-methoxyethoxy)phenyl]propanoate used as startingmaterial was prepared as follows:

To 3-(3-hydroxyphenyl)propionic acid (8.31 g, 50 mmol, 1 eq) inN,N-dimethylformamide (150 ml) was added potassium carbonate (17.28 g,125 mmol, 3 eq) followed by 2-bromoethyl methyl ether (10.34 ml, 110mmol, 2.20 eq). The reaction mixture was stirred overnight at roomtemperature. The reaction mixture was evaporated to dryness. The residuewas extracted into ethyl acetate, washed with water and brine, driedwith magnesium sulphate, filtered and evaporated to yield a yellow oil˜11.38 g. The reaction mixture was purified by column chromatographyusing a gradient of 0-30% ethyl acetate in hexanes. To this intermediate(9.82 g, 43.76 mmol, 1 eq) was added N,N-dimethylformamide (50 ml)followed by potassium carbonate (9.1 g, 65.64 mmol, 2.5 eq) and2-bromoethyl methyl ether (4.94 ml, 52.5 mmol, 1.2 eq). The reactionmixture was heated at 60° C. for 18 h. The reaction mixture was dilutedwith N,N-dimethylformamide (50 ml) and a further 4.55 g of potassiumcarbonate was added followed by 2-bromoethyl methyl ether (2.45 ml). Thereaction mixture was heated overnight at 60° C. for a further 20 h.After cooling to room temperature, the inorganics were filtered and thesolvent was evaporated under reduced pressure. The residue was extractedinto ethyl acetate and the organic layers was washed with water,saturated sodium hydrogen carbonate and brine. After drying (magnesiumsulphate) and filtration, the organic layers were evaporated underreduced pressure to yield a yellow oil. The crude product was purifiedby column chromatography, eluting with a gradient of 0-50% ethyl acetatein hexanes. The desired product was obtained as a clear yellow oil(8.755 g, 71%).

¹H NMR (300.132 MHz, DMSO) δ 2.63 (2H, t), 2.82 (2H, t), 3.25 (3H, s),3.31 (3H, s), 3.50 (2H, m), 3.65 (2H, m), 4.06 (2H, m), 4.13 (2H, dd),6.73-6.82 (3H, m), 7.18 (1H, t); MS: m/z 283 (MH+).

Example 74-(4-methylpiperazin-1-yl)-N-[5-(2-pyridin-3-ylethyl)-2H-pyrazol-3-yl]benzamide

Prepared in an analogous way to Example 1 but starting with5-(2-pyridin-3-ylethyl)-2H-pyrazol-3-amine (189 mg, 1 mmol, 1.5 eq) togive the above titled compound as a white solid (15 mg, 6% yield)

¹H NMR (300.132 MHz, DMSO) δ 2.23 (3H, s), 2.44 (4H, t), 2.89-2.98 (4H,m), 3.28 (4H, t), 6.40 (1H, s), 6.96 (2H, d), 7.28-7.33 (1H, m), 7.65(1H, dt), 7.89 (2H, d), 8.40 (1H, dd), 8.45 (1H, d), 10.31 (1H, s),12.09 (1H, s). MS m/z 391 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.047 μM.

5-(2-pyridin-3-ylethyl)-2H-pyrazol-3-amine, used as starting materialwas prepared as follows:

Acetonitrile (2.9 ml, 54.8 mmol, 1.3 eq) was added to a slurry of sodiumhydride (2.2 g, 54.8 mmol, 1.3 eq) in anhydrous 1,4-dioxane (50 ml). Tothis was then added a solution of methyl 3-pyridin-3-ylpropanoate (6.96g, 42 mmol, 1 eq) in anhydrous 1,4-dioxane (50 ml). The reaction washeated under reflux for 18 h. After cooling, ethanol (5 ml) was added,followed by hydrazine.HCl (3181 mg, 46.43 mmol, 1.1 eq). The reactionmixture was heated at 100° C. for 20 h, allowed to cool to roomtemperature and then evaporated under reduced pressure. The orangeresidue was dissolved in water (50 ml) and partioned with ethyl acetate(2×75 ml) The organic layers were combined and washed with 2M HCl. Theaqueous acidic layers were combined and washed with ethyl acetate. Theaqueous layer was separated, basified by the addition of 8N ammoniasolution and extracted with ethyl acetate. The organic layer was washedwith brine, dried with magnesium sulphate, filtered and evaporated underreduced pressure to yield the title compound as an orange oil. The oilwas dissolved in acetonitrile (10 ml) and purified on basicreverse-phase hplc using a 2-20% gradient of acetonitrile in water(containing 1% ammonium hydroxide). Desired fractions were combined andevaporated to yield the title compound (348 mg, 5% yield).

¹H NMR (400.132 MHz, DMSO) δ 2.74 (2H, t), 2.87 (2H, t), 4.43 (2H, s),5.17 (1H, s), 7.29 (1H, ddd), 7.61 (1H, dddd), 8.39 (1H, dd), 8.42 (1H,d), 11.08 (1H, s). MS; m/z 189 (MH+).

Further product was obtained from the basified aqueous layer bypurification using basic reverse-phase prep. HPLC. After evaporation ofthe desired fractions under reduced pressure to low volume, the solutionwas acidified using 2M HCl. The product was captured onto a SCX-2column. The product was column was eluted using 10% ammonia solution inmethanol. After evaporation under reduced pressure a yellow oil wasobtained (657 mg, 9% yield).

Example 8N-[5-[2-(2-furyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

Prepared in an analogous way to Example 1 but starting with5-[2-(2-furyl)ethyl]-2H-pyrazol-3-amine (178 mg, 1 mmol, 1.5 eq) to givethe above titled compound as a tan solid (24.8 mg, 10% yield).

¹H NMR (300.132 MHz, DMSO) δ 2.23 (3H, s), 2.44 (4H, t), 2.89-2.98 (4H,m), 3.28 (4H, t), 6.40 (1H, s), 6.96 (2H, d), 7.28-7.33 (1H, m), 7.65(1H, dt), 7.89 (2H, d), 8.40 (1H, dd), 8.45 (1H, d), 10.31 (1H, s),12.09 (1H, s). MS; m/z 380 (MH+).

Mean of n=1, FGFR Kinase assay—Elisa, IC₅₀ 0.0795 μM.

5-[2-(2-furyl)ethyl]-2H-pyrazol-3-amine, used as starting material wasprepared as follows:

a) A mixture of ethyl 2-triphenylphosphoranylideneacetate (34.84 g, 100mmol, 1 eq) and furan-2-carbaldehyde (9609 mg, 100 mmol, 1 eq) inanhydrous THF (200 ml) was stirred at room temperature for 24 h. Thesolvent was evaporated under reduced pressure and the residue trituratedwith ether to produce a brown solution and a precipitate. The solid wasfiltered, washed and removed. The filtrate was then evaporated. Theproduct was purified by column chromatography on silica eluting with0-20% ethyl acetate in hexanes. The desired fractions were evaporated toyield a cis/trans mixture of ethyl (E)-3-(2-furyl)prop-2-enoate as apale yellow oil (NMR suggested mainly trans product) (15.5 g, 93%).

b) A cis/trans mixture of ethyl (E)-3-(2-furyl)prop-2-enoate (15.5 g,93.27 mmol, 1 eq) was stirred in ethanol (120 ml) containing 10%palladium on charcoal (775 mg, 5% by w). The reaction mixture wasstirred under hydrogen for 4 h. A further quantity of 10% Pd/C (775 mg,5% by w) was added. The reaction was stirred under hydrogen for anadditional 95 mins. The reaction was filtered and evaporated underreduced pressure. The crude product was purified by silica columnchromatography eluting with 20% ethyl acetate in hexanes. The desiredfractions were evaporated under reduced pressure and ethyl3-(2-furyl)propanoate was obtained as a clear oil (3.69 g, 24% yield).

¹H NMR (300.132 MHz, CDCl3) δ 1.25 (3H, t), 2.64 (2H, t), 2.97 (2H, t),4.15 (2H, q), 6.02 (1H, td), 6.27 (1H, dd), 7.30 (1H, dd)

5-[2-(2-furyl)ethyl]-2H-pyrazol-3-amine (2.09 g, 54% over 2 steps) wasthen prepared in an analogous manner to that described for the startingmaterial for example 2 (5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-amine)using ethyl 3-(2-furyl)propanoate (6.33 g, 37.64 mmol, 1 eq) as startingmaterial.

¹H NMR (300.132 MHz, CDCl3) δ 2.98 (4H, t), 3.45 (2H, s), 6.04 (1H, d),6.28 (1H, dd), 7.30 (1H, dd). MS m/z 178 (MH+).

Example 9N-[5-[2-(3-furyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

Prepared in an analogous way to Example 1 but starting with5-[2-(3-furyl)ethyl]-2H-pyrazol-3-amine (178 mg, 1 mmol, 1.5 eq) to givethe title compound as a tan solid (17.3 mg, 7% yield).

¹H NMR (300.132 MHz, DMSO) δ 2.23 (3H, s), 2.45 (4H, t), 2.67-2.89 (4H,m), 3.28 (4H, t), 6.39 (1H, d), 6.43 (1H, s), 6.96 (2H, d), 7.45 (1H,s), 7.56 (1H, t), 7.89 (2H, d), 10.29 (1H, s), 12.07 (1H, s). MS m/z 380(MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.137 μM.

5-[2-(3-furyl)ethyl]-2H-pyrazol-3-amine (3.94 g, 59% over final 2steps), used as starting material was prepared in an analogous manner tothe synthesis of 5-[2-(2-furyl)ethyl]-2H-pyrazol-3-amine shown inexample 8.

Example 10N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

Prepared in an analogous way to Example 1, but starting with5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (566 mg, 2.30 mmol,1.5 eq) to give the title compound as a beige solid (183.5 mg, 27%yield).

¹H NMR (300.132 MHz, DMSO) δ 2.23 (3H, s), 2.44 (4H, t), 2.86 (4H, s),3.27 (4H, t), 3.72 (6H, s), 6.32 (2H, t), 6.35-6.42 (3H, m), 6.96 (2H,d), 7.89 (2H, d), 10.31 (1H, s), 12.08 (1H, s). MS: m/z 450 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00085 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 11N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

Prepared in an analogous way to Example 1, but starting with5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-amine (148 mg, 0.68 mmol, 1.5eq) to give the title compound as a solid (8.2 mg, 4% yield).

¹H NMR (300.132 MHz, DMSO) δ 2.23 (3H, s), 2.44 (4H, t), 2.89 (4H, s),3.26-3.31 (4H, m), 3.73 (3H, s), 6.16 (1H, s), 6.69-6.86 (3H, m), 6.96(2H, d), 7.20 (1H, t), 7.89 (2H, d), 10.31 (1H, s), 12.08 (1H, s). MSm/z 420 (MH+)

Mean of n=1, FGFR Kinase assay—Elisa, IC₅₀ 0.0828 μM.

5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-amine used as startingmaterial was prepared as follows:—

Acetonitrile (3.36 ml, 64.25 mmol, 1 eq) was added to a slurry of sodiumhydride (2.57 g dispersion in mineral oil, 64.25 mmol, 1 eq) inanhydrous 1,4-dioxane (50 ml) and the mixture was stirred at roomtemperature for 20 mins. Methyl 3-(3-methoxyphenyl)propanoate (10.4 g,53.54 mmol, 1 eq) in 1,4-dioxane (25 ml) was added and the reaction wasrefluxed for 2 h. The reaction mixture was cooled and quenched withwater. The residue was dissolved in 2M HCl and extracted into ethylacetate. The organic layer was separated, washed with 2M HCl, water andbrine and dried over magnesium sulphate. Evaporation under reducedpressure gave yield to a yellow oil, which was purified by silica columnchromatography, eluting with a mixture of 0-50% ethyl acetate inhexanes. Fractions containing the product were combined and evaporatedto leave 5-(3-methoxyphenyl)-3-oxo-pentanenitrile (5.37 g, 49% yield).

¹H NMR (300.132 MHz, CDCl3) δ 2.86 (4H, s), 3.32 (2H, s), 3.73 (3H, s),6.64-6.72 (3H, m), 7.14 (1H, t)

To 5-(3-methoxyphenyl)-3-oxo-pentanenitrile (5.37 g, 26.42 mmol, 1 eq)in ethanol (80 ml) was added hydrazine hydrate (1.41 ml, 29.06 mmol, 1.1eq). The reaction was refluxed for 3.5 h then allowed to cool. Themixture was evaporated under reduced pressure. The residue was dissolvedin ethyl acetate and the organic layer was washed with water, brine,dried with magnesium sulphate, filtered and evaporated to yield a yellowoil (which solidified on standing). This was acidified and purified bySCX-3 column chromatography. The compound was eluted with 10% ammonia inmethanol. After evaporation5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-amine was obtained (5.48 g,96% yield).

¹H NMR (300.132 MHz, DMSO): δ 2.64-2.87 (4H, m), 3.73 (3H, s), 4.40 (1H,s), 5.19 (1H, s), 6.71-6.82 (3H, m), 7.18 (1H, t), 11.07 (1H, s). MS;m/z 218 (MH+)

Example 12N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

Prepared in an analogous way to Example 1 but starting with5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride togive the title compound as a beige solid (34 mg, 13% yield).

¹H NMR (300.132 MHz, DMSO) δ 2.23 (3H, s), 2.44 (4H, t), 3.27-3.32 (4H,m), 3.75 (6H, s), 5.07 (2H, s), 5.57 (1H, s), 6.44-6.45 (1H, m), 6.59(2H, d), 7.01 (2H, d), 7.85 (2H, d), 10.64 (1H, s), 11.54 (1H, s). MSm/z 452 (MH+)

Mean of n=3, FGFR Kinase assay—Elisa, IC₅₀ 0.06 μM.

5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as follows:

3-Amino-5-hydroxypyrazole (8 g, 80.74 mmol) and triphenylphosphine(25.45 g, 96.88 mmol) were stirred in DCM (110 ml) under nitrogen andthe mixture was cooled in an ice-bath. Diisopropylazodicarboxylate(19.08 ml, 96.88 mmol) was added dropwise (temperature <10° C.) and thereaction mixture was stirred in the ice-bath for 1 h.3,5-Dimethoxybenzyl alcohol (16.30 g, 96.88 mol) in DCM (35 ml) wasadded dropwise, the reaction mixture was allowed to warm to roomtemperature and stirred under nitrogen for 4 days. The mixture wasfiltered, washed with DCM and the filtrate was extracted with 1M HCl(aq) (3×50 ml). The combined aqueous extracts were washed with DCM (50ml), resulting in precipitation of the product. The product wascollected by filtration, washed with water, DCM and dried under vacuumto afford the title compound as a white solid (358 mg, 1.8% yield). Afurther crop of product was obtained following precipitation from theinitial DCM layer on allowing to stand at room temperature. The solidproduct was collected by filtration, washed with DCM and dried undervacuum to give an off-white solid (1.127 g, 5.6% yield).

¹H NMR (300.132 MHz, DMSO) δ 3.75 (s, 6H), 5.18 (s, 2H), 5.26 (s, 1H),6.50 (t, 1H), 6.60 (d, 2H). MS: m/z 250 (MH+)

Example 13N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-methyl-pyridine-3-carboxamide

5-[2-(3-methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73mmol) was dissolved in toluene (10 ml) and to this was added methyl6-methylpyridine-3-carboxylate (122 mg, 0.73 mmol) and AlMe₃ (0.93 ml,1.8 mmol). The reaction mixture was stirred overnight. The reactionmixture was diluted with DCM (15 ml) and quenched with damp sodiumsulfite (care); the reaction was stirred for 20 mins before beingfiltered and the solvent removed in vacuo to yield a yellow gum. Thiswas dissolved in formic acid (12 ml) and heated at 82° C. overnight. Thereaction mixture was evaporated to dryness and the resulting product waspassed through a SCX column, eluting initially with methanol followed by2N ammonia/methanol. After removal of the solvent a yellow solid wasobtained which was triturated with hot acetonitrile to afford a whitesolid. The solid was filtered and dried (117 mg, 48%).

¹H NMR (400.132 MHz, DMSO) δ 2.54 (s, 3H), 2.91 (s, 4H), 3.74 (s, 3H),6.45 (s, 1H), 6.76 (d, 1H), 6.83-6.82 (m, 2H), 7.20 (t, 1H), 7.36 (d,1H), 8.21 (dd, 1H), 9.01 (s, 1H), 10.81 (s, 1H), 12.21 (s, 1H); MS: m/z409 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.95 μM.

5-[2-(3-methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine, used asstarting material was prepared as follows:

The crude 5-(3-methoxy-phenyl)-3-oxo-pentanenitrile (10 g, 0.049 mol),t-butylhydrazine HCl (7.29 g, 0.059 mol) and TEA (8.20 ml, 0.059 mol)were dissolved in ethanol (300 ml) and heated at reflux for 3 h. Thereaction mixture was cooled and solvent removed in vacuo to yield aviscous brown oil; this was quenched with water (100 ml), extracted withdiethyl ether (3×200 ml), dried (MgSO₄) and solvent removed in vacuo toyield a dark orange oil. This was purified via distillation at 165° C. @0.40 mbar to afford a clear viscous oil which solidified on standing.

¹H NMR (400.132 MHz, CDCl3) δ 1.55 (s, 9H), 2.76-2.71 (m, 2H), 2.85-2.80(m, 2H), 3.40 (brs, 2H), 3.72 (s, 3H), 5.31 (s, 1H), 6.66 (dd, 1H), 6.71(s, 1H), 6.76 (d, 1H), 7.11 (t, 1H);

MS: m/z 274 (MH+).

5-(3-Methoxy-phenyl)-3-oxo-pentanenitrile, used as starting material wasprepared as follows:

LDA (34 ml, 0.068 mol) was added to THF (300 ml) and cooled to −78° C.under a nitrogen atmosphere, to this was slowly added acetonitrile (2.8g, 0.068 mol) in THF (20 ml). The reaction was stirred for 10 mins at−78° C. before the rapid addition of methyl3-(3-methoxyphenyl)propanoate (10 g, 0.052 mol). The reaction wasstirred for 30 mins before being allowed to warm up to room temperature.The reaction was quenched with 1.0 N HCl (100 ml), extracted withdiethyl ether (2×200 ml), dried (MgSO₄) and solvent removed in vacuo toyield a yellow gum. This appeared to slowly decompose and was usedimmediately in the next step.

Example 146-Methoxy-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide

Prepared in an analogous manner to Example 13 except using methyl6-methoxypyridine-3-carboxylate as a starting material (168 mg, 65%).

¹H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.74 (s, 3H), 3.93 (s, 3H),6.45 (s, 1H), 6.77-6.75 (m, 1H), 6.83-6.81 (m, 2H), 6.90 (d, 1H), 7.20(t, 1H), 8.25 (dd, 1H), 8.81 (d, 1H), 10.70 (s, 1H), 12.17 (s, 1H); MS:m/z 353 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.61 μM.

Example 15N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-methylsulfonyl-benzamide

Prepared in an analogous manner to Example 13 except using ethyl4-methylsulfonylbenzoate as a starting material (82 mg, 28%).

¹H NMR (400.132 MHz, DMSO) δ 2.91 (s, 4H), 3.28 (s, 3H), 3.74 (s, 3H),6.49 (s, 1H), 6.78-6.75 (m, 1H), 6.84-6.81 (m, 2H), 7.20 (t, 1H), 8.03(d, 2H), 8.20 (d, 2H), 10.96 (s, 1H), 12.23 (s, 1H); MS: m/z 400 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.11 μM.

Example 16N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-methyl-pyrazine-2-carboxamide

Prepared in an analogous manner to Example 13 except using_methyl5-methylpyrazine-2-carboxylate as a starting material (63 mg, 26%).

¹H NMR (400.132 MHz, DMSO) δ 2.62 (s, 3H), 2.91 (s, 4H), 3.73 (s, 3H),6.48 (s, 1H), 6.77-6.75 (m, 1H), 6.85-6.80 (m, 2H), 7.20 (t, 1H), 8.67(s, 1H), 9.13 (s, 1H), 10.26 (s, 1H), 12.28 (s, 1H); MS: m/z 338 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.75 μM.

Example 17N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(prop-2-ynylamino)pyridine-2-carboxamide

Prepared in an analogous manner Example 13 except using_methyl5-(prop-2-ynylamino)pyridine-2-carboxylate as a starting material (39mg, 14%).

¹H NMR (400.132 MHz, CDCl3) δ 2.28 (t, 1H), 2.96 (s, 4H), 3.77 (s, 3H),4.00 (s, 2H), 4.56 (s, 1H), 6.47 (s, 1H), 6.76-6.73 (m, 2H), 6.78 (d,1H), 7.04 (dd, 1H), 7.21-7.17 (m, 1H), 7.96 (d, 1H), 8.09 (d, 1H), 10.14(s, 1H), NH missing; MS: m/z 376 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.66 μM.

Example 186-Ethylamino-N-{5-[2-(3-methoxy-phenyl)-ethyl]-2H-pyrazol-3-yl}-nicotinamide

Prepared in an analogous manner to Example 13 exceptusing_6-ethylamino-nicotinic acid methyl ester as a starting material(44 mg, 16%).

¹H NMR (400.132 MHz, DMSO) δ 1.15 (t, 3H), 2.89 (s, 4H), 3.35-3.30 (m,2H), 3.74 (s, 3H), 6.46-6.42 (m, 2H), 6.77-6.75 (m, 1H), 6.82-6.81 (m,2H), 7.06 (s, 1H), 7.20 (t, 1H), 7.93 (d, 1H), 8.65 (s, 1H), 10.28 (s,1H), 12.06 (s, 1H); MS: m/z 366 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.54 μM.

Example 194-Acetamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

5-[2-(3-methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73mmol) was dissolved in THF/pyridine (5 ml/1 ml), to this was added4-acetamidobenzoyl chloride (190 mg, 0.95 mmol) and the reaction mixturewas stirred overnight. The reaction mixture was evaporated to dryness,purified by column chromatography, eluting with 0-5% MeOH in DCM, andevaporated to afford a white foam. The residue was dissolved in formicacid (12 ml) and heated at 82° C. overnight. The reaction mixture wasevaporated to dryness and the product was purified by a SCX column.Removal of the solvent gave a yellow solid, which was triturated withhot acetonitrile to afford a white solid. The solid was filtered anddried in vacuo (16 mg, 6%); MS: m/z 378 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.40 μM.

5-[2-(3-methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine used asstarting material was prepared as indicated in Example 13.

Example 20N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)pyrazine-2-carboxamide

NaHMDS (1M solution in THF, 0.645 ml, 0.644 mmol, 1.5 eq) was addeddropwise to a stirred suspension of tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (150 mg,0.429 mmol, 1 eq) and methyl5-(4-methylpiperazin-1-yl)pyrazine-2-carboxylate (122 mg, 0.515 mmol,1.2 eq) in dry THF (2.5 ml) under nitrogen. The reaction mixture wasstirred at room temperature for 50 min, then neutralised with satd aqNH₄Cl and diluted with water (5 ml). The aqueous phase was extractedwith ethyl acetate (3×8 ml) and the combined organic extracts were driedover MgSO₄, filtered and evaporated. The residual solid was purified byreverse-phase prep. HPLC using a gradient of 31-51% acetonitrile inwater containing 1% ammonium hydroxide to afford the product as a whitesolid (88 mg, 45%).

¹H NMR (399.902 MHz, DMSO) δ 2.24 (s, 3H), 2.41-2.46 (m, 4H), 3.72-3.78(m, 4H), 3.75 (s, 6H), 5.08 (s, 2H), 5.84 (s, 1H), 6.44 (t, 1H), 6.59(d, 2H), 8.33 (s, 1H), 8.72 (s, 1H), 10.81 (s, 1H), 11.35 (s, 1H). MS:m/z 454 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.046 μM.

Methyl 5-(4-methylpiperazin-1-yl)pyrazine-2-carboxylate, used asstarting material was prepared as follows:

Methyl 5-chloropyrazine-2-carboxylate (100 mg, 0.579 mmol, 1 eq),1-methylpiperazine (65 μl, 0579 mmol, 1 eq) and potassium carbonate (161mg, 1.159 mmol, 2 eq) were heated in DMSO in a microwave reactor at 120°C. for 5 min. The reaction mixture was poured onto an SCX column (10 g),washed with methanol then eluted with 2M ammonia in methanol. Thereaction was repeated as above with methyl5-chloropyrazine-2-carboxylate (150 mg), 1-methylpiperazine (98 μl) andpotassium carbonate (241 mg) in DMSO (3 ml). The product fractions fromboth reactions were combined and evaporated under vacuum to afford theproduct as a yellow solid (283 mg, 83%).

¹H NMR (399.902 MHz, DMSO) δ 2.23 (s, 3H), 2.42 (t, 4H), 3.73 (t, 4H),3.82 (s, 3H), 8.38 (d, 1H), 8.66 (d, 1H). MS: m/z 237 (MH+).

Example 214-Benzamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

5-[2-(3-Methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73mmol) was dissolved in toluene (10 ml) and to this was added methyl4-benzamidobenzoate (200 mg, 0.80 mmol) and AlMe₃ (0.93 ml, 1.8 mmol).The reaction was stirred overnight. The reaction was diluted with DCM(15 ml) and quenched with damp sodium sulfite. The reaction mixture wasstirred for 20 mins before being filtered and the solvent removed invacuo to yield a yellow gum. This gum was dissolved in formic acid (12ml) and heated at 82° C. overnight. The reaction was evaporated todryness and the resulting product was passed through a SCX column,eluting initially with methanol followed by 2N ammonia/methanol. Afterremoval of the solvent, a yellow solid was obtained which was trituratedwith hot acetonitrile to afford a white solid. The solid was filteredand dried (66 mg, 21%); 1H NMR (400.132 MHz, DMSO) δ 2.91 (s, 4H), 3.74(s, 3H), 6.46 (brs, 1H), 6.77 (d, 1H), 6.83 (s, 2H), 7.20 (t, 1H),7.64-7.54 (m, 3H), 7.90 (d, 2H), 8.02-7.97 (m, 4H), 10.46 (s, 1H), 10.55(s, 1H), 12.15 (s, 1H); MS: m/z 441 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 231 μM.

Example 226-(2-Methoxyethoxy)-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide

6-Chloro-N-[5-[2-(3-methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-yl]pyridine-3-carboxamide(0.15 g, 0.36 mmol) was added to a tube and dissolved in2-methoxyethanol (15 ml). NaH (51 mg, 1.0 mmol) was added and thereaction was heated at 80° C. overnight. The reaction mixture wasevaporated to dryness and passed through a SCX column, eluting initiallywith methanol followed by 2N ammonia/methanol. The eluant was evaporatedto dryness. The obtained gum was then dissolved in formic acid andheated at 80° C. overnight. The reaction was evaporated to dryness andpassed through a SCX column, eluting initially with methanol followed by2N ammonia/methanol. The eluant was evaporated to dryness and theresulting gum was purified by reverse-phase prep. HPLC (basic) using a30-50% gradient of acetonitrile in water containing 1% ammoniumhydroxide solution. The product was obtained as solid (19 mg, 13%); ¹HNMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.31 (s, 3H), 3.69-3.67 (m, 2H),3.74 (s, 3H), 4.47-4.44 (m, 2H), 6.45 (s, 1H), 6.76 (d, 1H), 6.82 (s,2H), 6.90 (d, 1H), 7.20 (t, 1H), 8.25 (d, 1H), 8.78 (s, 1H), 10.69 (s,1H), 12.17 (s, 1H); MH+ 397.

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.72 μM.

6-Chloro-N-[5-[2-(3-methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-yl]pyridine-3-carboxamide,used as starting material was prepared as per Example 21 using methyl6-chloropyridine-3-carboxylate (1.02 g, 33%); ¹H NMR (400.132 MHz,CDCl3) δ 1.65 (s, 9H), 2.98-2.88 (m, 4H), 3.79 (s, 3H), 6.20 (brs, 1H),6.73 (dd, 1H), 6.79 (s, 1H), 6.83 (d, 1H), 7.19 (t, 1H), 7.52-7.47 (m,2H), 8.12 (brs, 1H), 8.83 (brs, 1H); MS: m/z 413 (MH+).

Example 234-Cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

tert-Butyl5-[(4-cyanobenzoyl)amino]-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylatewas added to acetonitrile (5 ml) and 6.0 N HCl in propan-2-ol (10 ml).The reaction mixture was stirred overnight to afford a white solid,which was filtered and dissolved in methanol/water. The solution wasthen passed through a SCX column. On removal of the solvent in vacuo awhite solid was obtained (0.29 g, 67%); ¹H NMR (400.132 MHz, DMSO) δ2.91 (s, 4H), 3.74 (s, 3H), 6.48 (s, 1H), 6.76 (d, 1H), 6.83 (s, 2H),7.20 (t, 1H), 7.97 (d, 2H), 8.12 (d, 2H), 10.95 (s, 1H), 12.24 (s, 1H);MH+ 347.

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 28.6 μM.

tert-Butyl5-[(4-cyanobenzoyl)amino]-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate,used as starting material was prepared as follows:

tert-Butyl 5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate(0.4 g, 1.26 mmol) was dissolved in DCM/pyridine (6 ml, 5:1) and to thiswas added 4-cyanobenzoyl chloride (0.27 g, 0.95 mmol). The reactionmixture was stirred overnight. The reaction mixture was evaporated todryness to afford a black gum which was used in the next step withoutany further purification.

tert-butyl 5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate,used as starting material was prepared as follows:

5-[2-(3-Methoxy-phenyl)-ethyl]-2H-pyrazol-3-ylamine (5 g, 23 mmol) andBoc anhydride (6.5 g, 30 mmol) were dissolved in DCM (200 ml) andstirred overnight at room temperature. The reaction mixture wasevaporated to dryness and dissolved in diethyl ether. To this was addediso-hexane and the solvent was slowly removed in vacuo until a solid wasvisible. The solution was scratched and sonicated to afford tert-butyl5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate (6.3 g, 86%)as a white solid; ¹H NMR (400.132 MHz, CDCl3) δ 7.20 (t, 1H), 6.82 (d,1H), 6.79 (s, 1H), 6.74 (d, 1H), 5.22 (s, 1H), 3.79 (s, 3H), 2.93-2.88(m, 2H), 2.86-2.81 (m, 2H), 1.65 (s, 9H); MH+ 318.

Example 24N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzene-1,4-dicarboxamide

4-Cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide(Example 23) (0.2 g, 0.58 mmol) and NaOH (69 mg, 1.73 mmol) were addedto a solution of ethanol/water (20 ml, 3:1) and heated at 80° C. untilcomplete consumption of starting material was observed. Care wasrequired as the amide further hydrolysed to the carboxylic acid. Thereaction was extracted with DCM (3×50 ml), dried and the solvent wasremoved in vacuo to yield a white solid. This was triturated with DCM toafford a white solid (20 mg, 10%); ¹H NMR (400.132 MHz, DMSO) δ 2.90 (s,4H), 3.75 (s, 3H), 6.42 (s, 1H), 6.82-6.75 (m, 3H), 7.20 (t, 1H), 7.46(s, 1H), 7.95 (d, 2H), 8.16-8.03 (m, 3H), 10.82 (s, 1H), 12.18 (s, 1H);MH+ 366.

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.43 μM.

Example 25N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-pyrazol-1-yl-benzamide

5-[2-(3-Methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73mmol) was dissolved in toluene (10 ml) and to this was added methyl4-pyrazol-1-ylbenzoate (177 mg, 0.88 mmol) and AlMe₃ (0.93 ml, 1.8mmol). The reaction mixture was stirred overnight. The reaction mixturewas diluted with DCM (15 ml), quenched with damp sodium sulfite andfurther stirred for 20 mins before being filtered. The solvent wasremoved in vacuo to yield a yellow gum. This gum was dissolved in formicacid (12 ml) and heated at 82° C. overnight. The reaction mixture wasevaporated to dryness and the resulting product was passed through a SCXcolumn, eluting initially with methanol followed by 2N ammonia/methanol.After solvent removal, a yellow solid was obtained which was trituratedwith hot acetonitrile to afford a white solid. The solid was filteredand dried (155 mg, 55%); ¹H NMR (400.132 MHz, DMSO) δ 2.92 (s, 4H), 3.74(s, 3H), 6.48 (s, 1H), 6.60 (s, 1H), 6.77 (d, 1H), 6.84-6.82 (m, 2H),7.20 (t, 1H), 7.81 (s, 1H), 7.96 (d, 2H), 8.14 (d, 2H), 8.63 (s, 1H),10.69 (s, 1H), 12.18 (s, 1H); MS: m/z 388 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.94 μM.

Example 266-Anilino-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide

Prepared using an analogous method to example 25, but starting withmethyl 6-anilinopyridine-3-carboxylate (200 mg, 0.88 mmol) to give thetitle compound (106 mg, 35%);

¹H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.74 (s, 3H), 6.44 (s, 1H),6.76 (d, 1H), 6.87-6.82 (m, 3H), 6.97 (t, 1H), 7.20 (t, 1H), 7.31 (t,2H), 7.70 (d, 2H), 8.11 (d, 1H), 8.79 (s, 1H), 9.41 (s, 1H), 10.51 (s,1H), 12.13 (s, 1H); MH+ 414

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 64 μM.

Example 274-Methanesulfonamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

Prepared using an analogous method to example 25, but starting withmethyl 4-methanesulfonamidobenzoate (200 mg, 0.88 mmol) to give thetitle compound (125 mg, 41%);

¹H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.06 (s, 3H), 3.74 (s, 3H),6.42 (s, 1H), 6.76 (d, 1H), 6.83-6.82 (m, 2H), 7.20 (t, 1H), 7.24 (d,2H), 7.97 (d, 2H), 10.54 (s, 1H), 12.09 (vbrs, 1H); MH+ 416

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.26 μM.

Example 284-(Hydroxymethyl)-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

Prepared using an analogous method to example 25, but starting withmethyl 4-(hydroxymethyl)benzoate (146 mg, 0.88 mmol) to give the titlecompound (136 mg, 53%); ¹H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.74(s, 3H), 4.57 (d, 2H), 5.28 (t, 1H), 6.45 (s, 1H), 6.76 (d, 1H),6.83-6.82 (m, 2H), 7.20 (t, 1H), 7.41 (d, 2H), 7.95 (d, 2H), 10.58 (s,1H), 12.14 (s, 1H); MH+ 352.

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.074 μM.

Example 295-Formamido-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-2-carboxamide

Prepared using an analogous method to example 25, but starting withmethyl 5-[(2-methylpropan-2-yl)oxycarbonylamino]pyridine-2-carboxylate(222 mg, 0.88 mmol) to give the title compound (72 mg, 27%); ¹H NMR(400.132 MHz, DMSO) δ 2.91 (s, 4H), 3.73 (s, 3H), 6.47 (s, 1H), 6.76 (d,1H), 6.83-6.82 (m, 2H), 7.20 (t, 1H), 8.12 (d, 1H), 8.26 (dd, 1H), 8.44(s, 1H), 8.87 (s, 1H), 10.13 (vbrs, 1H), 10.74 (s, 1H), 12.23 (s, 1H);MH+ 366

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.87 μM.

Example 304-(Dimethylsulfamoyl)-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

Prepared using an analogous method to example 25, but starting withmethyl 4-(dimethylsulfamoyl)benzoate (214 mg, 0.88 mmol) to give thetitle compound (126 mg, 40%);

¹H NMR (400.132 MHz, DMSO) δ 2.66 (s, 6H), 2.91 (s, 4H), 3.74 (s, 3H),6.49 (s, 1H), 6.77 (d, 1H), 6.83-6.82 (m, 2H), 7.20 (t, 1H), 7.85 (d,2H), 8.20 (d, 2H), 10.93 (s, 1H), 12.23 (s, 1H); MH+ 429.

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.80 μM.

Example 316-Hydroxy-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide

Prepared using an analogous method to example 25, but starting withmethyl 6-hydroxypyridine-3-carboxylate (147 mg, 0.88 mmol) to give thetitle compound (28 mg, 11%);

¹H NMR (400.132 MHz, DMSO) δ 2.89 (s, 4H), 3.73 (s, 3H), 6.37-6.34 (m,2H), 6.76 (d, 1H), 6.82-6.80 (m, 2H), 7.19 (t, 1H), 7.97 (dd, 1H), 8.18(d, 1H), 10.44 (s, 1H), 12.03 (vbrs, 1H); MH+ 339

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 1.05 μM.

Example 32N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-morpholin-4-yl-pyridine-3-carboxamide

Prepared using an analogous method to example 25, but starting withmethyl 6-morpholin-4-ylpyridine-3-carboxylate (195 mg, 0.88 mmol) togive the title compound (140 mg, 47%); ¹H NMR (400.132 MHz, DMSO) δ 2.90(s, 4H), 3.59-3.57 (m, 4H), 3.71-3.69 (m, 4H), 3.74 (s, 3H), 6.44 (s,1H), 6.76 (d, 1H), 6.82-6.81 (m, 2H), 6.86 (d, 1H), 7.20 (t, 1H), 8.13(d, 1H), 8.76 (s, 1H), 10.45 (s, 1H), 12.11 (s, 1H); MH+ 408

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.027 μM.

Methyl 6-morpholin-4-ylpyridine-3-carboxylate, used as starting materialwas prepared as follows:

6-Morpholin-4-ylpyridine-3-carboxylic acid (2.56 g, 13.6 mmol) andpotassium carbonate (2.8 g, 20.4 mmol) were added to DMF (40 ml) and tothis was added MeI (0.97 ml, 15 mmol). The reaction mixture was heatedat 50° C. for 3 h. The solvent was removed in vacuo to yield a darksolid, which was quenched with 2.0N NaOH (100 ml), extracted with DCM(3×100 ml), dried (MgSO₄) and solvent removed in vacuo to yield a brownsolid. This solid was dissolved in hot acetonitrile and allowed to coolto afford a white solid, which was filtered and the process repeated onthe mother liquor to obtain the title compound (1.8 g, 60%); 1H NMR(400.132 MHz, CDCl3) 3.65 (t, 4H), 3.81 (t, 4H), 3.87 (s, 3H), 6.53 (d,1H), 8.04 (dd, 1H), 8.80 (d, 1H); MH+ 223.

Example 33N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1,3-oxazol-5-yl)benzamide

Prepared using an analogous method to example 25, but starting withmethyl 4-(1,3-oxazol-5-yl)benzoate (177 mg, 0.88 mmol) to give the titlecompound (28 mg, 10%); ¹H NMR (400.132 MHz, DMSO) δ 2.91 (s, 4H), 3.74(s, 3H), 6.48 (s, 1H), 6.77 (d, 1H), 6.82 (m, 2H), 7.20 (t, 1H),7.87-7.83 (m, 3H), 8.10 (d, 2H), 8.51 (s, 1H), 10.73 (s, 1H), 12.18 (s,1H); MH+ 389.

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 1.2 μM.

Example 34N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(tetrazol-1-yl)benzamide

Prepared using an analogous method to example 25, but starting withmethyl 4-(tetrazol-1-yl)benzoate (179 mg, 0.88 mmol) to give the titlecompound (16 mg, 6%); ¹H NMR (400.132 MHz, DMSO) δ 2.92 (s, 4H), 3.74(s, 3H), 6.50 (s, 1H), 6.77 (d, 1H), 6.84-6.82 (m, 2H), 7.21 (t, 1H),8.06 (d, 2H), 8.25 (d, 2H), 10.19 (s, 1H), 10.89 (s, 1H), 12.22 (s, 1H);MH+ 390.

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 1 μM.

Example 35 Prop-2-enylN-[5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridin-2-yl]carbamate

Prepared using an analogous method to example 25, but starting withmethyl 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylate (208 mg, 0.88mmol) to give the title compound (38 mg, 12%); ¹H NMR (400.132 MHz,DMSO) δ 2.90 (s, 4H), 3.74 (s, 3H), 4.66 (d, 2H), 5.25 (d, 1H), 5.40 (d,1H), 6.02-5.95 (m, 1H), 6.46 (s, 1H), 6.76 (d, 1H), 6.84-6.80 (m, 2H),7.20 (t, 1H), 7.91 (d, 1H), 8.32 (d, 1H), 8.87 (s, 1H), 10.56 (s, 1H),10.74 (s, 1H), 12.17 (s, 1H); MH+ 422.

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 76 μM.

Methyl 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylate, used asstarting material was prepared in an analogous manner to the synthesisof methyl 6-morpholin-4-ylpyridine-3-carboxylate in Example 32, butstarting with 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylic acidcarboxylate (880 mg, 3.96 mmol) to give the title compound (0.35 g,37%); 1H NMR (400.132 MHz, CDCl3) 3.93 (s, 3H), 4.75 (dt, 2H), 5.32 (dq,1H), 5.41 (dq, 1H), 6.09-5.99 (m, 1H), 8.07 (d, 1H), 8.30 (dd, 1H), 8.97(d, 1H), 9.45 (brs, 1H); MH+ 237.

Example 36N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1,2,4-triazol-1-yl)benzamide

Prepared using an analogous method to example 25, but starting withmethyl 4-(1,2,4-triazol-1-yl)benzoate (177 mg, 0.88 mmol) to give thetitle compound (83 mg, 29%); ¹H NMR (400.132 MHz, DMSO) δ 2.92 (s, 4H),3.74 (s, 3H), 6.48 (s, 1H), 6.77 (d, 1H), 6.83-6.82 (m, 2H), 7.20 (t,1H), 8.00 (d, 2H), 8.19 (d, 2H), 8.29 (s, 1H), 9.42 (s, 1H), 10.79 (s,1H), 12.20 (s, 1H); MH+ 389.

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.66 μM.

Example 37N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-pyrazol-1-yl-pyridine-3-carboxamide

Prepared using an analogous method to example 25, but starting withmethyl 6-pyrazol-1-ylpyridine-3-carboxylate (177 mg, 0.88 mmol) to givethe title compound (151 mg, 54%); ¹H NMR (400.132 MHz, DMSO) δ 2.92 (s,4H), 3.74 (s, 3H), 6.49 (s, 1H), 6.63 (dd, 1H), 6.77 (d, 1H), 6.83-6.82(m, 2H), 7.20 (t, 1H), 7.90 (s, 1H), 8.01 (d, 1H), 8.52 (d, 1H), 8.70(s, 1H), 9.03 (s, 1H), 10.95 (s, 1H), 12.23 (s, 1H); MH+ 389.

Mean of n=3, FGFR Kinase assay—Caliper, IC₅₀ 69 μM.

Methyl 6-pyrazol-1-ylpyridine-3-carboxylate, used as starting materialwas prepared as follows:

Pyrazole (2.4 g, 35.4 mmol) was added to DMA (100 ml) and to this wasslowly added NaH (1.85 g, 38.6 mmol). The reaction mixture was stirredfor 10 mins under a nitrogen atmosphere. To the resulting anion wasadded methyl 6-chloropyridine-3-carboxylate (5.5 g, 32.2 mmol) and thereaction was heated at 95° C. overnight. The reaction mixture wasevaporated to dryness, quenched with 2.0 N NaOH (100 ml), extracted withDCM (3×100 ml), dried (MgSO₄) and the solvent removed in vacuo to yielda brown solid. This solid was purified via silica column chromatography,eluting with 0-40% diethyl ether in iso-hexane. A white solid wasobtained, which was dissolved in hot iso-hexane. On cooling a whitesolid was obtained which was filtered and dried (2.6 g, 40%); ¹H NMR(400.132 MHz, CDCl3) δ 3.96 (s, 3H), 6.50 (s, 1H), 7.77 (s, 1H), 8.05(d, 1H), 8.40 (dd, 1H), 8.62 (d, 1H), 9.02 (d, 1H); MH+ 203.

Example 38N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluoro-benzamide

Oxalyl chloride (2M in DCM, 1.40 ml, 2.75 mmol, 1.1 eq) was addeddropwise to a mixture of 4-fluorobenzoic acid (350 mg, 2.50 mmol, 1 eq)in dichloromethane (15 ml) at 0° C. containing a few drops of DMF (10ul, 0.12 mmol, 0.05 eq) and DIPEA (937 μl, 5.25 mmol, 2.1 eq). Afterstirring for 60 mins at 0° C. a solution of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (742 mg, 3 mmol, 1.2eq) in DCM (10 ml) was added dropwise over 15 mins. The mixture wasmaintained at 0° C. for a further 2 h, then gradually allowed to warm toroom temperature overnight. The mixture was diluted with DCM (50 ml) andwashed with aqueous NaHCO₃ solution (50 ml). The aqueous layer wasextracted with DCM (50 ml). The combined organic layers were collectedand concentrated. The crude product was purified by reverse-phase prepHPLC using a 30-50% gradient of acetonitrile in water containing 1%ammonium hydroxide solution. The desired fractions were evaporated toafford the title compound as a beige solid. (31.5 mg, 3% yield)

¹H NMR (300.132 MHz, DMSO) δ 2.87 (4H, s), 3.72 (6H, s), 6.32 (1H, t),6.42 (2H, d), 6.46 (1H, s), 7.31 (2H, t), 8.06 (2H, m), 10.69 (1H, s),12.16 (1H, s). MS: m/z 370 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.165 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as shown in the starting material preparation inExample 2.

Example 39N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-3-methoxy-benzamide

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (89 μl, 0.67 mmol, 1.05 eq)was added dropwise to 3-methoxybenzoic acid (97 mg, 0.63 mmol, 1 eq) inDCM (1.5 ml) at ambient temperature. After stirring at ambienttemperature for 1.5 h, a solution of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (199mg, 0.57 mmol, 0.9 eq) and pyridine (142 μL, 1.74 mmol, 2.75 eq) in DCM(2 ml) was added to the reaction mixture and stirring was continued atambient temperature for a further 3 h. A solution of TFA (386 μL, 5.2mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continuedat ambient temperature for 18 h. The reaction mixture was concentratedand the crude product was purified by reverse-phase prep. HPLC (basic)using a gradient of acetonitrile in water containing 1% ammoniumhydroxide solution. The clean fractions were taken and evaporated toafford the title compound as a colourless solid (129 mg, 59% yield). ¹HNMR (399.902 MHz, DMSO) δ 2.89 (4H, s), 3.73 (6H, s), 3.84 (3H, s),6.34-6.33 (1H, m), 6.43 (2H, d), 6.48 (1H, s), 7.12-7.10 (1H, m),7.42-7.37 (1H, m), 7.59-7.56 (2H, m), 10.65 (1H, br.s), 12.16 (1H,br.s). MS: m/z 382 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.37 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 40N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-3-morpholin-4-yl-benzamide

Prepared in an analogous way to Example 39, starting with3-morpholin-4-ylbenzoic acid (130 mg, 0.63 mmol) to give the titlecompound as a solid (105 mg, 42% yield); ¹H NMR (399.902 MHz, DMSO) δ2.89 (4H, s), 3.21-3.19 (4H, m), 3.73 (6H, s), 3.79-3.76 (4H, m),6.34-6.33 (1H, m), 6.43 (2H, d), 6.48 (1H, s), 7.12 (1H, d), 7.35-7.31(1H, m), 7.43 (1H, d), 7.57 (1H, s), 10.62 (1H, br.s), 12.15 (1H, br.s).MS: m/z 437 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.71 μM.

Example 41N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-2-methoxy-benzamide

Prepared in an analogous way to Example 39, starting with2-methoxybenzoic acid (95.8 mg, 0.63 mmol) to give the title compound asa solid (100 mg, 46% yield); ¹H NMR (399.902 MHz, DMSO) δ 2.89 (4H, s),3.73 (6H, s), 3.97 (3H, s), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.49 (1H,s), 7.12-7.07 (1H, m), 7.21 (1H, d), 7.56-7.51 (1H, m), 7.85-7.82 (1H,m), 10.16 (1H, br.s), 12.14 (1H, br.s). MS: m/z 382 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 2.61 μM.

Example 42N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-ethoxyethoxy)benzamide

Prepared in an analogous way to Example 39, starting with4-(2-ethoxyethoxy)benzoic acid (132 mg, 0.63 mmol) to give the titlecompound as a solid (126 mg, 50% yield); ¹H NMR (399.902 MHz, DMSO) δ1.15 (3H, t), 2.88 (4H, s), 3.52 (2H, q), 3.73 (8H, s), 4.19-4.16 (1H,m), 6.34-6.32 (1H, m), 6.43 (2H, d), 6.46 (1H, s), 7.02 (2H, d), 7.98(2H, d), 10.47 (1H, br.s), 12.11 (1H, br.s). MS: m/z 440 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.075 μM.

Example 43N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(1-piperidyl)benzamide

Prepared in an analogous way to Example 39, starting with4-(1-piperidyl)benzoic acid (129 mg, 0.63 mmol) to give the titlecompound as a solid (97.5 mg, 39% yield);

¹H NMR (399.902 MHz, DMSO) δ 1.60 (6H, s), 2.88 (4H, s), 3.33-3.31 (6H,m), 3.73 (1H, s), 6.33-6.32 (2H, m), 6.42 (1H, d), 6.45 (2H, s), 6.94(2H, d), 10.26 (1H, br.s), 12.07 (1H, br.s).

MS: m/z 435 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.438 μM.

Example 44N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-piperidylmethoxy)benzamide

Prepared in an analogous way to Example 39, starting with4-[[1-[(2-methylpropan-2-yl)oxycarbonyl]-4-piperidyl]methoxy]benzoicacid (211 mg, 0.63 mmol) to give the title compound as a solid (40 mg,15% yield); ¹H NMR (399.902 MHz, DMSO) δ^(˜)1.72-1.67 (2H, m), 1.87-1.79(2H, m), 2.48-2.45 (1H, m), 2.88 (4H, s), 2.98-2.94 (2H, m), 3.73 (6H,s), 3.88 (2H, d), 6.34 (1H, s), 6.46-6.42 (3H, m), 7.00 (2H, d), 7.97(2H, d), 10.48 (1H, br.s), 12.14 (1H, br.s). MS: m/z 465 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.025 μM.

Example 45N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-piperazin-1-yl-benzamide

Prepared in an analogous way to Example 39, starting with4-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]benzoic acid (193mg, 0.63 mmol) to give the title compound as a solid (100 mg, 40%yield); ¹H NMR (399.902 MHz, DMSO) δ 2.84-2.82 (4H, m), 2.88 (4H, s),3.21-3.15 (4H, m), 3.73 (6H, s), 6.33 (1H, s), 6.46-6.42 (3H, m), 6.94(2H, d), 7.89 (2H, d), 10.30 (1H, br.s), 12.09 (1H, br.s). MS: m/z 436(MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.026 μM.

Example 46N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-6-piperazin-1-yl-pyridine-3-carboxamide

Prepared in an analogous way to Example 39, starting with6-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]pyridine-3-carboxylicacid (193 mg, 0.63 mmol) to give the title compound as a solid (96 mg,39% yield); ¹H NMR (399.902 MHz, DMSO) δ 2.79-2.76 (4H, m), 2.88 (4H,s), 3.56-3.53 (4H, m), 3.73 (6H, s), 6.34-6.32 (1H, m), 6.45-6.42 (3H,m), 6.82 (1H, d), 8.10-8.07 (1H, m), 8.73 (1H, d), 10.43 (1H, br.s),12.12 (1H, br.s). MS: m/z 437 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.040 μM.

Example 47N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(dimethylaminomethyl)benzamide

Oxalyl chloride (61 μl, 0.69 mmol, 1.1 eq) was added dropwise to4-(dimethylaminomethyl)benzoic acid (113 mg, 0.63 mmol, 1 eq) in DCM(2.5 ml) containing 1 drop of DMF. After stirring at ambient temperaturefor 1.5 h, a solution of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (196 mg,0.56 mmol, 0.9 eq) and pyridine (137 μL, 1.69 mmol, 2.70 eq) in DCM (2ml) was added to the reaction mixture and stirring was continued atambient temperature for a further 2 h. A solution of TFA (384 μL, 5.16mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continuedat ambient temperature for 18 h. The reaction mixture was concentratedand the crude product was purified by reverse-phase prep. HPLC (basic)using a gradient of acetonitrile in water containing 1% ammoniumhydroxide solution. The clean fractions were taken and evaporated toafford the title compound as a colourless solid (65 mg, 25% yield); ¹HNMR (399.902 MHz, DMSO) δ 2.09 (6H, s), 2.81 (4H, s), 3.38 (2H, s), 3.65(6H, s), 6.26-6.25 (1H, m), 6.35 (2H, d), 6.40 (1H, s), 7.31 (2H, d),7.87 (2H, d), 10.51 (1H, br.s), 12.07 (1H, br.s). MS: m/z 409 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.019 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate, used asstarting material was prepared as in Example 2.

1H NMR (399.902 MHz, DMSO) δ1.56 (9H, s), 2.68-2.63 (2H, m), 2.80-2.75(2H, m), 3.73 (6H, s), 5.22 (1H, s), 6.23 (2H, br.s), 6.32-6.31 (1H, m),6.44 (2H, d). MS: m/z 370 ([M+Na]+).

Example 48N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-hydroxyethoxy)benzamide

A solution of NaHMDS in THF (1 M, 1.15 ml, 1.15 mmol, 2 eq) was addeddropwise at ambient temperature to a mixture oftert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate(200 mg, 0.58 mmol, 1 eq) and methyl 4-(2-hydroxyethoxy)benzoate (136mg, 0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirredat ambient temperature for 1 h. It was then concentrated and the crudeproduct was purified by reverse-phase prep. HPLC (basic) using agradient of acetonitrile in water containing 1% ammonium hydroxidesolution. The clean fractions were taken and evaporated to afford thetitle compound as a colourless solid (29 mg, 12% yield); ¹H NMR (399.902MHz, DMSO) δ 2.89 (4H, s), 3.77-3.72 (8H, m), 4.07 (2H, t), 4.88 (1H,t), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.46 (1H, s), 7.01 (2H, d), 7.98(2H, d), 10.46 (1H, br.s), 12.12 (1H, br.s). MS: m/z 412 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.039 μM.

tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate,used as starting material was prepared as in Example 2.

Example 494-(2-Aminopropyl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide

A solution of NaHMDS in THF (1 M, 0.86 ml, 0.86 mmol, 1.5 eq) was addeddropwise at ambient temperature to a mixture oftert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate(200 mg, 0.58 mmol, 1 eq) and methyl 4-(2-aminopropyl)benzoate (133 mg,0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirred atambient temperature for 2 h. It was then concentrated and the crudeproduct was purified by reverse-phase prep. HPLC (basic) using agradient of acetonitrile in water containing 1% ammonium hydroxidesolution. The clean fractions were taken and evaporated to afford thetitle compound as a pale yellow gum (10 mg, 4% yield); ¹H NMR (399.902MHz, DMSO) δ 0.89 (3H, d), 2.53-2.47 (2H, m), 2.80 (4H, s), 3.01-2.93(1H, m), 3.65 (6H, s), 6.25-6.24 (1H, m), 6.34 (2H, d), 6.40 (1H, s),7.21 (2H, d), 7.84 (2H, d), 10.47 (1H, br.s), 12.06 (1H, br.s). MS: m/z409 (MH+)

Cell FGFR1, IC₅₀ 1.47 μM.

tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate,used as starting material was prepared as in Example 2.

Example 50N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3,3-dimethyl-1-piperidyl)methyl]benzamide

Prepared in an analogous way to Example 49, starting with methyl4-[(3,3-dimethyl-1-piperidyl)methyl]benzoate (180 mg, 0.69 mmol) to givethe title compound as a colourless solid (44 mg, 16% yield); ¹H NMR(399.902 MHz, DMSO) δ 0.92 (3H, s), 1.23-1.20 (2H, m), 1.59-1.52 (2H,m), 2.01-1.99 (2H, m), 2.35-2.29 (2H, m), 2.89 (4H, s), 3.48 (2H, s),3.73 (6H, s), 6.34-6.32 (1H, m), 6.43 (2H, d), 6.48 (1H, s), 7.40 (2H,d), 7.94 (2H, d), 10.57 (1H, br.s), 12.14 (1H, br.s). MS: m/z 477 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.001 μM.

Methyl 4-[(3,3-dimethyl-1-piperidyl)methyl]benzoate, used as startingmaterial was prepared as follows:

3,3-Dimethylpiperidine (170 mg, 1.5 mmol, 1.5 eq) was added in oneportion to a mixture of methyl 4-(bromomethyl)benzoate (230 mg, 1 mmol,1 eq) and MP-carbonate (2.74 mmol/g, 1.46 g, 4 mmol, 4 eq) in MeCN (5ml). The reaction mixture was stirred at ambient temperature for 18 h.Polymer-supported isocyanate (1 mmol/g, 1 g, 1 mmol, 1 eq) was added inone portion and stirring continued for 4 h. The reaction mixture wasfiltered, the resins washed with MeCN and the combined filtrate wasconcentrated to afford a clear liquid (216 mg, 83% yield); ¹H NMR(399.902 MHz, DMSO) δ 0.91 (6H, s), 1.22-1.19 (2H, m), 1.58-1.52 (2H,m), 1.99 (2H, s), 2.33-2.28 (2H, m), 3.49 (2H, s), 3.85 (3H, s), 7.46(2H, d), 7.92 (2H, d).

MS: m/z 262 (MH+)

Example 51N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[4-(2-hydroxyethyl)piperazin-1-yl]benzamide

Prepared in an analogous way to Example 49, starting with methyl4-[4-(2-hydroxyethyl)piperazin-1-yl]benzoate (182 mg, 0.69 mmol) to givethe title compound as a colourless solid (11 mg, 4% yield); ¹H NMR(399.902 MHz, DMSO) δ 2.45 (2H, t), 2.58-2.55 (4H, m), 2.88 (4H, s),3.29-3.26 (4H, m), 3.58-3.53 (2H, m), 3.73 (6H, s), 4.42 (1H, t),6.34-6.32 (1H, m), 6.42 (2H, d), 6.45 (1H, s), 6.96 (2H, d), 7.90 (2H,d), 10.30 (1H, br.s), 12.08 (1H, br.s). MS: m/z 480 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.081 μM.

Methyl 4-[4-(2-hydroxyethyl)piperazin-1-yl]benzoate, used as startingmaterial was prepared as follows:

Trimethylsilyldiazomethane solution (2M in hexanes, 1.2 ml, 2.4 mmol,1.2 eq) was added dropwise to4-(4-[2-hydroxyethyl]piperazin-1-yl)benzoic acid (501 mg, 2 mmol, 1 eq)in toluene (14 ml) and methanol (4 ml) at ambient temperature. Thereaction mixture was allowed to stir for 5 h, the solvent removed underreduced pressure and the residue dried under high vacuum to affordmethyl 4-(2-bromoethoxy)benzoate as a cream solid (342 mg, 65% yield).MS: m/z 265 (MH+)

Example 524-[(7-Cyano-3,4-dihydro-1H-isoquinolin-2-yl)methyl]-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide

Prepared in an analogous way to Example 53, starting with methyl4-[(7-cyano-3,4-dihydro-1H-isoquinolin-2-yl)methyl]benzoate (211 mg,0.69 mmol) to give the title compound as a pale yellow gum (45 mg, 15%yield); ¹H NMR (399.902 MHz, DMSO) δ^(˜) 2.67-2.64 (2H, m), 2.81 (4H,s), 2.86-2.83 (2H, m), 3.54 (2H, s), 3.67-3.64 (8H, m), 6.26-6.24 (1H,m), 6.35 (2H, d), 6.41 (1H, s), 7.26 (1H, d), 7.39 (2H, d), 7.51-7.47(2H, m), 7.91 (2H, d), 10.53 (1H, br.s), 12.07 (1H, br.s). MS: m/z 522(MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.486 μM.

Methyl 4-[(7-cyano-3,4-dihydro-1H-isoquinolin-2-yl)methyl]benzoate, usedas starting material was prepared as follows:

1,2,3,4-tetrahydroisoquinoline-7-carbonitrile hydrochloride (292 mg, 1.5mmol, 1.5 eq) was added in one portion to a mixture of methyl4-(bromomethyl)benzoate (230 mg, 1 mmol, 1 eq) and MP-carbonate (2.74mmol/g, 1.46 g, 4 mmol, 4 eq) in MeCN (5 ml). The reaction mixture wasstirred at ambient temperature for 18 h. Polymer-supported isocyanate (1mmol/g, 1 g, 1 mmol, 1 eq) was added in one portion and stirringcontinued for 4 h. The reaction mixture was filtered, the resins washedwith MeCN and the combined filtrate was concentrated to afford a paleyellow oil which solidified on standing overnight (292 mg, 95% yield);¹H NMR (399.902 MHz, DMSO) δ^(˜) 2.70-2.63 (2H, m), 2.89-2.82 (2H, m),3.53 (2H, s), 3.68 (2H, s), 3.78 (3H, s), 7.25 (1H, d), 7.51-7.38 (4H,m), 7.89-7.86 (2H, m). MS: m/z 307 (MH+)

Example 53N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3-fluoro-1-piperidyl)methyl]benzamide

A solution of NaHMDS in THF (1 M, 0.86 ml, 0.86 mmol, 1.5 eq) was addeddropwise at ambient temperature to a mixture oftert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate(200 mg, 0.58 mmol, 1 eq) and methyl4-[(3-fluoro-1-piperidyl)methyl]benzoate (174 mg, 0.69 mmol, 1.2 eq) inTHF (1 ml). The reaction mixture was stirred at ambient temperature for2 h. The reaction mixture was then concentrated and the crude productwas purified by reverse-phase prep. HPLC (acidic) using a gradient ofacetonitrile in water containing 0.1% TFA. The clean fractions weretaken and evaporated. The residue was dissolved in 3:1 DCM:MeCN mixture(4 ml) and MP-carbonate (2.74 mmol/g, 1 g, 2.74 mmol) was added. Themixture was stirred for 4 h, filtered and the filtrate evaporated toafford the title compound as a pale yellow gum (43 mg, 16% yield); ¹HNMR (399.902 MHz, DMSO) δ^(˜) 1.46-1.34 (2H, m), 1.82-1.61 (2H, m),2.36-2.28 (2H, m), 2.66-2.56 (2H, m), 2.81 (4H, s), 3.50 (2H, s), 3.65(6H, s), 4.66-4.47 (1H, m), 6.26-6.24 (1H, m), 6.35 (2H, d), 6.40 (1H,s), 7.32 (2H, d), 7.88 (2H, d), 10.51 (1H, br.s), 12.07 (1H, br.s).

MS: m/z 467 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.090 μM.

Methyl 4-[(3-fluoro-1-piperidyl)methyl]benzoate, used as startingmaterial was prepared as follows:

3-Fluoropiperidine hydrochloride (210 mg, 1.5 mmol, 1.5 eq) was added inone portion to a mixture of methyl 4-(bromomethyl)benzoate (230 mg, 1mmol, 1 eq) and MP-carbonate (2.74 mmol/g, 1.46 g, 4 mmol, 4 eq) in MeCN(5 ml). The reaction mixture was stirred at ambient temperature for 18h. Polymer-supported isocyanate (1 mmol/g, 1 g, 1 mmol, 1 eq) was addedin one portion and stirring continued for 4 h. The reaction mixture wasfiltered, the resins washed with MeCN and the combined filtrate wasconcentrated to afford a clear oil, 217 mg, 86% yield.

¹H NMR (399.902 MHz, DMSO) δ^(˜) 1.59-1.42 (2H, m), 1.90-1.67 (2H, m),2.42-2.36 (2H, m), 2.73-2.63 (2H, m), 3.59 (2H, s), 3.86 (3H, s),4.73-4.56 (1H, m), 7.46 (2H, d), 7.93 (2H, d). MS: m/z 252 (MH+)

tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate,used as starting material was prepared as in Example 2.

Example 54N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-morpholin-4-ylethoxy)benzamide

Prepared in an analogous way to Example 53, starting with methyl4-(2-morpholin-4-ylethoxy)benzoate (183 mg, 0.69 mmol) to give the titlecompound as a pale yellow gum (21 mg, 7.5% yield); ¹H NMR (399.902 MHz,CDCl3) δ^(˜) 2.59-2.57 (4H, m), 2.81 (2H, t), 2.99-2.90 (4H, m),3.75-3.72 (4H, m), 3.77 (6H, s), 4.14 (2H, t), 6.36-6.32 (4H, m), 6.67(1H, br.s), 6.96 (2H, d), 7.83 (2H, d), 8.53 (1H, br.s). MS: m/z 481(MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.096 μM.

Methyl 4-(2-morpholin-4-ylethoxy)benzoate, used as starting material wasprepared as follows:

MP-Carbonate (2.74 mmol/g, 529 mg, 1.45 mmol, 1.5 eq) was added tomethyl 4-(2-bromoethoxy)benzoate (250 mg, 0.96 mmol, 1 eq), morpholine(93 μl, 1.06 mmol, 1.1 eq), sodium iodide (150 mg, 1 mmol, 1.05 eq) andMeCN (5 ml) were charged to a microwave reactor vessel and the reactionmixture heated to 120° C. in a microwave reactor for 10 minutes. Thereaction mixture was transferred to a SCX-2 cartridge, eluted with MeOHfollowed by 3.5 N ammonia in MeOH solution. The latter fractions werecombined and evaporated to afford a clear oil which solidified onstanding to a cream solid (146 mg, 57% yield). ¹H NMR (400.132 MHz,CDCl3) δ 2.59-2.57 (4H, m), 2.82 (2H, t), 3.74-3.72 (4H, m), 3.88 (3H,s), 4.16 (2H, t), 6.93-6.91 (2H, m), 7.99-7.97 (2H, m). MS: m/z 266(MH+)

Example 554-[2-(4,4-Difluoro-1-piperidyl)ethoxy]-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide

Prepared in an analogous way to Example 53, starting with methyl4-[2-(4,4-difluoro-1-piperidyl)ethoxy]benzoate (104 mg, 0.35 mmol) togive the title compound as a clear gum (5 mg, 1.7% yield); ¹H NMR(399.902 MHz, CDCl3) δ 2.06-1.96 (4H, m), 2.70-2.67 (4H, m), 2.88-2.85(2H, m), 2.97-2.92 (4H, m), 3.77-3.76 (8H, m), 4.12 (2H, t), 6.33-6.32(2H, m), 6.35-6.35 (2H, m), 6.65 (1H, br.s), 6.95 (2H, d), 7.83 (2H, d),8.59 (1H, s). MS: m/z 515 (MH+)

Cell FGFR1, IC₅₀ 0.46 μM.

Methyl 4-[2-(4,4-difluoro-1-piperidyl)ethoxy]benzoate, used as startingmaterial was prepared as follows:

MP-Carbonate (2.74 mmol/g, 1.234 g, 3.38 mmol, 2.5 eq) was added tomethyl 4-(2-bromoethoxy)benzoate (350 mg, 1.35 mmol, 1 eq),4,4-difluoropiperidine hydrochloride (235 mg, 1.49 mmol, 1.1 eq), sodiumiodide (212 mg, 1.42 mmol, 1.05 eq) and MeCN (6 ml) were charged to amicrowave reactor vessel and the reaction mixture heated to 120° C. in amicrowave reactor for 10 minutes. The reaction mixture was transferredto a SCX-2 cartridge, eluted with MeOH followed by 3.5 N ammonia in MeOHsolution. The latter fractions were combined and evaporated to afford acolourless solid (104 mg, 35% yield).

¹H NMR (400.132 MHz, CDCl3) δ^(˜) 2.08-1.98 (4H, m), 2.74-2.71 (4H, m),2.90 (2H, t), 3.89 (3H, s), 4.16 (2H, t), 6.93-6.91 (2H, m), 8.00-7.98(2H, m). MS: m/z 300 (MH+)

Example 56N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(2-morpholin-4-ylethyl)benzamide

Prepared in an analogous way to Example 53, starting with methyl4-(2-morpholin-4-ylethyl)benzoate (172 mg, 0.69 mmol) to give the titlecompound as a clear gum (42 mg, 15.6% yield); ¹H NMR (399.902 MHz, DMSO)δ^(˜)2.3 7-2.35 (4H, m), 2.49-2.45 (2H, m), 2.73 (2H, t), 2.80 (4H, s),3.50 (4H, t), 3.65 (6H, s), 6.26-6.24 (1H, m), 6.34 (2H, d), 6.40 (1H,s), 7.26 (2H, d), 7.83 (2H, d), 10.47 (1H, br.s), 12.06 (1H, br.s). MS:m/z 465 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.120 μM.

4-(2-Morpholin-4-ylethyl)benzoic acid, used as starting material wasprepared as follows: Trimethylsilyldiazomethane solution (2M in hexanes,1.2 ml, 2.4 mmol, 1.2 eq) was added dropwise to 4-(2-bromoethyl)benzoicacid (459 mg, 2 mmol, 1 eq) in toluene (14 ml) and methanol (4 ml) atambient temperature. The reaction mixture was allowed to stir for 5 h,the solvent removed under reduced pressure and the residue dried underhigh vacuum to afford methyl 4-(2-bromoethoxy)benzoate as a pale yellowliquid (487 mg, 100% yield).

¹H NMR (399.902 MHz, DMSO) δ 3.20 (2H, t), 3.76 (2H, t), 3.83 (3H, s),7.42 (2H, d), 7.89 (2H, d).

MP-carbonate (2.74 mmol/g, 270 mg, 0.74 mmol, 0.6 eq) was added tomethyl 4-(2-bromoethoxy)benzoate (300 mg, 1.23 mmol, 1 eq), morpholine(0.12 ml, 1.36 mmol, 1.1 eq), sodium iodide (193 mg, 1.29 mmol, 1.05 eq)and MeCN (6 ml) were charged to a microwave reactor vessel and thereaction mixture heated to 120° C. in a microwave reactor for 10minutes. The reaction mixture was transferred to an SCX-2 cartridge,eluted with MeOH followed by 3.5 N ammonia in MeOH solution. The latterfractions were combined and evaporated to afford a pale yellow solid(130 mg, 52% yield).

¹H NMR (399.902 MHz, CDCl3) δ 2.53-2.51 (4H, m), 2.64-2.60 (2H, m),2.88-2.84 (2H, m), 3.75-3.72 (4H, m), 3.90 (3H, s), 7.28-7.26 (2H, m),7.97-7.94 (2H, m). MS: m/z 250 (MH+)

Example 57N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(methyl-(oxolan-2-ylmethyl)amino)methyl]benzamide

Prepared in an analogous way to Example 53, starting with methyl4-[(methyl-(oxolan-2-ylmethyl)amino)methyl]benzoate (181 mg, 0.69 mmol)to give the title compound as a clear gum (56 mg, 20% yield); ¹H NMR(399.902 MHz, DMSO) δ 1.56-1.42 (1H, m), 1.81-1.74 (2H, m), 1.98-1.90(1H, m), 2.20 (3H, s), 2.44 (2H, d), 3.31 (4H, s), 3.66-3.59 (3H, m),3.73 (6H, s), 4.01-3.94 (2H, m), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.48(1H, s), 7.40 (2H, d), 7.95 (2H, d), 10.58 (1H, br.s), 12.15 (1H, br.s).MS: m/z 479 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0053 μM.

Methyl 4-[(methyl-(oxolan-2-ylmethyl)amino)methyl]benzoate, used asstarting material was prepared as follows:

MP-carbonate (2.74 mmol/g, 1.44 g, 4 mmol, 2 eq) was added to methyl4-(bromomethyl)benzoate (500 mg, 2 mmol, 1 eq),N-methyl-1-(oxolan-2-yl)methanamine (231 mg, 2 mmol, 1 eq) and MeCN (10ml). The reaction mixture was allowed to stir at ambient temperature for18 h and was then transferred to a SCX-2 cartridge, eluted with MeOHfollowed by 3.5 N ammonia in MeOH solution. The latter fractions werecombined and evaporated to afford a pale yellow solid (355 mg, 64%yield).

1H NMR (399.902 MHz, CDCl3) δ 1.54-1.47 (1H, m), 1.87-1.80 (2H, m),2.01-1.93 (1H, m), 2.28 (3H, s), 2.46-2.42 (1H, m), 2.55-2.50 (1H, m),3.68-3.57 (2H, m), 3.76-3.71 (1H, m), 3.87-3.81 (1H, m), 3.91 (3H, s),4.08-4.01 (1H, m), 7.41 (2H, d), 7.98 (2H, d). MS: m/z 264 (MH+)

Example 58N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-piperidyl)benzamide

Prepared in an analogous way to Example 53, starting with methyl4-(4-piperidyl)benzoate hydrochloride (176 mg, 0.69 mmol) to give thetitle compound as a pale yellow gum (20 mg, 8% yield); ¹H NMR (399.902MHz, DMSO) δ 1.69-1.57 (2H, m), 1.84-1.76 (2H, m), 2.76-2.68 (2H, m),2.93 (4H, s), 3.17-3.12 (2H, m), 3.77-3.76 (7H, m), 6.38-6.37 (1H, m),6.47 (2H, d), 6.53 (1H, s), 7.38 (2H, d), 7.98 (2H, d), 10.61 (1H, s),12.20 (1H, s). MS: m/z 435 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.001 μM.

Example 59N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-dimethylamino-benzamide

Prepared in an analogous way to Example 39, starting with4-dimethylaminobenzoic acid (102 mg, 0.63 mmol) to give the titlecompound as a solid (139 mg, 63% yield); ¹H NMR (399.902 MHz, DMSO) δ2.87 (4H, s), 3.00 (6H, s), 3.73 (6H, s), 6.33-6.32 (1H, m), 6.42 (2H,d), 6.45 (1H, s), 6.72 (2H, d), 7.89 (2H, d), 10.21 (1H, brs), 12.06(1H, br.s). MS: m/z 395 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.134 μM.

Example 60N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-5-piperazin-1-yl-thiophene-2-carboxamide(2,2,2-trifluoroacetic Acid Salt)

5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylicacid (150 mg, mmol) was dissolved in dry THF (10 ml) under nitrogen,1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (177 μl, mmol) was added andthe mixture was stirred at room temperature for 3.5 h. Tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl) ethyl]pyrazole-1-carboxylate (167 mg,mmol) and pyridine (47 μl, mmol) were added and the reaction was heatedto 65° C. for 18 h. The reaction mixture was then cooled to roomtemperature and 4M HCl in dioxane (2.0 ml, 2.0 mmol) added. The mixturewas stirred overnight at room temperature, evaporated and the residuewas purified by acidic prep. HPLC, eluting with a gradient of 24-32%MeCN in 0.1% TFA in water. The clean fractions were taken and evaporatedto give the title compound as a pale green solid (28.7 mg, 11%); ¹H NMR(399.902 MHz, DMSO) δ 2.79 (s, 4H), 3.21 (s, 4H), 3.34 (s, 4H), 3.64 (s,6H), 6.29 (m, 5H), 7.77 (m, 1H), 8.71 (s, 1H), 10.37 (s, 1H) MS: m/z=442(MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.022 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate, used asstarting material was prepared as in Example 2.

5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylicacid, used as starting material was prepared as follows:—

A solution of tert-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate(2.51 g, 8.50 mmol) in ethanol (85 ml) was added in one portion to asolution of silver (I) nitrate (10.0 g, 58.8 mmol) and sodium hydroxide(4.83 g, 120.6 mmol) in water (85 ml). This mixture was stirred andheated at 65° C. for 22 h. The mixture was cooled by the addition of iceand then filtered to remove silver salts. The filtrate was carefullyevaporated to remove the ethanol and the resulting aqueous solution wasfiltered again through a glass-fibre pad to remove tarry material. Thefiltrate was then diluted with water to a total volume of 400 ml andthen acidified to pH 5 with acetic acid. The precipitate was filteredoff, washed with water and then dried in a vacuum oven at 45° C.overnight to give5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylicacid (1.88 g, 71%).

1H NMR (399.9 MHz, DMSO-d₆) δ 1.41 (9H, s), 3.18 (4H, m), 3.45 (4H, m),6.20 (1H, d), 7.43 (1H, d)

MS: m/z 313 (MH+)

tert-Butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate, used asstarting material was prepared as follows:—

A mixture of 5-bromothiophene-2-carboxaldehyde (3.82 g, 20.0 mmol),tert-butyl piperazine-1-carboxylate (4.1 g, 22.0 mmol), N-ethyl-N,N-diisopropylamine (7.0 ml, 40.0 mmol) and dimethylsulphoxide (5.0 ml)were stirred at 130° C. under an atmosphere of nitrogen for 18 h. Thecooled mixture was partitioned between ethyl acetate and water. Theorganics were washed with water, brine, dried over magnesium sulphateand evaporated. The resultant dark red solid was purified by silicacolumn chromatography, eluting with dichloromethane followed by ethylacetate/dichloromethane (15%) to give tert-butyl4-(5-formylthien-2-yl)piperazine-1-carboxylate (4.3 g, 73%).

1H NMR (399.9 MHz, DMSO-d₆) δ 1.41 (9H, s), 3.34 (4H, m), 3.47 (4H, m),6.36 (1H, d), 7.70 (1H, d), 9.49 (1H, s)

MS: m/z 297 (MH+)

Example 61 Methyl6-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-3-carboxylate

5-Methoxycarbonylpyridine-2-carboxylic acid (0.285 g, 1.58 mmol) wasadded to DCM (40 ml), to this was added oxayl chloride (0.165 ml, 1.90mmol) and a few drops of anhydrous DMF. The reaction mixture was stirredfor 30 mins before the addition of tert-butyl5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate (0.50 g, 1.58mmol) and pyridine (2.0 ml). The reaction was stirred overnight. Thereaction was evaporated to dryness to give yield to a gum. To this gumwas added formic acid. The reaction mixture was stirred for 1 h beforebeing evaporated to dryness. The resulting gum was quenched withsaturated potassium carbonate (30 ml), extracted with DCM (3×50 ml),dried (MgSO₄) and the solvent removed in vacuo to yield a viscous gum.Trituration with acetonitrile gave the desired product as a Slightlyyellow solid (24 mg, 4%); ¹H NMR (400.132 MHz, DMSO) δ 2.92 (s, 4H),3.74 (s, 3H), 3.95 (s, 3H), 6.50 (s, 1H), 6.76 (d, 1H), 6.83-6.82 (m,2H), 7.20 (t, 1H), 8.26 (d, 1H), 8.53 (d, 1H), 9.17 (s, 1H), 10.38 (s,1H), 12.31 (s, 1H); MH+ 381.

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 68 μM.

tert-butyl 5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate,used as starting material was prepared as in Example 23.

4-(4-Methylpiperazin-1-yl)benzoyl chloride, used as starting materialwas prepared as follows:

To a suspension of 4-(4-methylpiperazin-1-yl)benzoic acid (500 mg, 2.27mmol, 1 eq) in DCM (20 ml) was added DMF (1 drop) followed by oxalylchloride (219 μl, 2.50 mmol, 1.1 eq) added dropwise. The mixture wasallowed to stir for 18 hours after which time the mixture wasconcentrated to dryness and taken through to the next stage with nofurther purification or characterisation.

Example 626-Chloro-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide

6-Bromopyridine-3-carboxylic acid (122 mg, 0.82 mmol, 1.3 eq) wasdissolved in DCM (5 mL) and oxalyl chloride (72 μL, 0.82 mmol, 1.3 eq)was added dropwise followed by a drop of DMF. The reaction was stirredfor 1 h at ambient temperature, then N,N-diethylethanamine (1 mL, 1.89mmol, 3 eq) was added followed by tert-butyl5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.63mmol, 1 eq). The reaction was stirred for 2 h, then diluted with DCM andwashed with water, brine, dried (MgSO₄), filtered and evaporated to givethe crude Boc-protected compound as a yellow gum. The gum was dissolvedin 2-propanol (5 mL) and a solution of 6M HCl in 2-propanol (4 mL) wasadded. The solution was stirred at ambient temperature overnight and wasthen evaporated to dryness and loaded onto a SCX-2 column. The columnwas washed with methanol and the product eluted with 2N ammonia inmethanol to give an orange solid. Trituration with a small volume ofmethanol gave6-chloro-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide(39 mg, 17%) as a white solid; ¹H NMR (400.13 MHz, DMSO) δ 2.89 (4H, s),3.74 (3H, s), 6.46 (1H, s), 6.75 (1H, m), 6.81 (2H, m), 7.20 (1H, t),7.65 (1H, d), 8.35 (1H, m), 8.95 (1H, d), 10.99 (1H, s), 12.23 (1H, s)MS m/z 357 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 4.54 μM.

tert-Butyl 5-amino-3-[2-(3-methoxyphenyl)ethyl]pyrazole-1-carboxylateused as starting material was prepared as outlined in Example 23.

Example 636-Cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-3-carboxamide

Preparation was analogous to that described for Example 62, except using6-cyanopyridine-3-carboxylic acid (122 mg, 0.82 mmol, 1.3 eq) asstarting material. After purification by SCX column, the material wasfurther purified by reverse-phase prep. HPLC (basic) using a 30-50%gradient of acetonitrile in water containing 1% ammonium hydroxidesolution. The clean fractions were taken and evaporated to afford thetitle compound as a cream solid. (58 mg, 27% yield); ¹H NMR (400.13 MHz,DMSO) δ 2.9 (4H, s), 3.74 (3H, s), 6.48 (1H, s), 6.75 (1H, m), 6.8 (2H,m), 7.2 (1H, t), 8.15 (1H, d), 8.52 (1H, m), 9.22 (1H, d), 11.19 (1H,s), 12.26 (1H, s) MS m/z 348 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 3.77 μM.

Example 644-Hydroxy-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyridine-2-carboxamide

Preparation was analogous to that described for Example 62, except using4-hydroxypyridine-2-carboxylic acid (114 mg, 0.82 mmol, 1.3 eq) asstarting material. After purification by SCX column, the material wasfurther purified by reverse-phase prep. HPLC (basic) using a 30-50%gradient of acetonitrile in water containing 1% ammonium hydroxidesolution. The clean fractions were taken and evaporated to afford thetitle compound as a white solid (10 mg, 5% yield); ¹H NMR (400.13 MHz,DMSO) δ^(˜) 2.9 (4H, s), 3.73 (3H, s), 6.47 (1H, s), 6.75 (1H, m), 6.8(2H, m), 6.92 (1H, s), 7.19 (1H, t), 7.47 (1H, s), 8.32 (1H, s), 10.2(1H, s), 12.21 (1H, s) MS m/z 339 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 5 μM.

Example 65N-[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-(2-pyrrolidin-1-ylethyl)pyridine-3-carboxamide

Preparation was analogous to that described for Example 62, except using6-(2-pyrrolidin-1-ylethyl)pyridine-3-carboxylic acid (180 mg, 0.82 mmol,1.3 eq) as starting material. After purification by SCX column, thematerial was further purified by reverse-phase prep. HPLC (basic) usinga 30-50% gradient of acetonitrile in water containing 1% ammoniumhydroxide solution. The clean fractions were taken and evaporated toafford the title compound as a white solid (5 mg, 2% yield); ¹H NMR(400.13 MHz, DMSO) δ^(˜) 1.66 (4H, m), 2.77 (2H, t), 2.89 (4H, s), 2.94(2H, t), 3.27 (4H, m), 3.73 (3H, s), 6.46 (1H, s), 6.75 (1H, m), 6.82(1H, m), 7.19 (1H, t), 7.40 (1H, d), 8.21 (1H, m), 9.01 (1H, d), 10.79(1H, s), 12.17 (1H, s) MS m/z 420 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.24 μM.

Example 665-[[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylicAcid

Preparation was analogous to that described for Example 62, except using6-methoxycarbonylpyridine-3-carboxylic acid (149 mg, 0.82 mmol, 1.3 eq)as starting material. After purification by SCX column, the material wasfurther purified by reverse-phase prep. HPLC (basic) using a 30-50%gradient of acetonitrile in water containing 1% ammonium hydroxidesolution. During this purification the ester hydrolysed to the acidproduct. The clean fractions were taken and evaporated to afford thetitle compound as a white solid (66 mg, 40% yield); ¹H NMR (400.13 MHz,DMSO) δ^(˜)2.90 (4H, s), 3.74 (3H, s), 6.46 (1H, s), 6.75 (1H, m), 6.83(2H, m), 7.19 (1H, t), 8.01 (1H, d), 9.12 (1H, d), 11.01 (1H, s), 12.2(1H, s) MS m/z 367 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 1.02 μM.

Example 67 Methyl5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylate

To a stirred suspension of5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylicacid (55 mg, 0.15 mmol, 1 eq) in methanol (0.5 mL) was added thionylchloride (23 uL, 0.32 mmol, 2.1 eq) dropwise. The resulting solution washeated at 50° C. for 3 h. The mixture was concentrated in vacuo to yieldan orange solid. This was dissolved in DCM and washed with saturatedaqueous sodium hydrogen carbonate and brine. The organic layers weredried over magnesium sulphate, filtered and concentrated to give thecrude product as a yellow solid. Trituration with diethyl ether gave thetitle compound as a white solid 27 mg (47%); ¹H NMR (400.13 MHz, DMSO)δ^(˜) 2.92 (4H, s), 3.74 (3H, s), 3.92 (3H, s), 6.49 (1H, s), 6.25 (1H,m), 6.82 (2H, m), 7.19 (1H, t), 8.14 (1H, d), 8.46 (1H, m), 9.20 (1H,d), 11.11 (1H, s), 12.25 (1H, s) MS m/z 381 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 2.86 μM.

5-[[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylicacid used as starting material was prepared as outlined in Example 66.

Example 68 Ethyl5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylate

Preparation was analogous to that described for Example 67, except using5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylicacid (55 mg, 0.15 mmol, 1 eq) in ethanol (0.5 mL) to give title compoundas a white solid (9 mg, 15% yield);

¹H NMR (400.13 MHz, DMSO) δ^(˜) 1.40 (3H, t), 2.97 (4H, s), 3.79 (3H,s), 4.44 (2H, q), 6.54 (1H, s), 6.8 (1H, m), 6.87 (2H, m), 7.25 (1H, t),8.19 (1H, d), 8.52 (1H, m), 9.25 (1H, s), 11.17 (1H, s), 12.3 (1H, s) MSm/z 395 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.724 μM.

5-[[5-[2-(3-Methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylicacid used as starting material was prepared as outlined in Example 66.

Example 69N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)pyridine-2-carboxamide

NaHMDS (1M solution in THF, 0.45 ml, 0.451 mmol, 1.5 eq) was addeddropwise to a stirred suspension of tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (105 mg,0.301 mmol, 1 eq) and methyl5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate (85 mg, 0.361 mmol, 1.2eq) in dry THF (2.5 ml) under nitrogen. The solution was stirred at roomtemperature for 1 h. The solution was neutralised with satd. aq. NH₄Cland diluted with water (5 ml). The aqueous phase was extracted withethyl acetate (3×8 ml) and the combined organic extracts were dried overMgSO₄, filtered and evaporated. The reaction was repeated as above on a0.338 mmol scale. The crude extracts were combined with those above andpurified on by silica column chromatography, eluting with 0-6% MeOH inDCM, to afford the title compound as a pale brown solid (92 mg, 35%yield); ¹H NMR (399.902 MHz, DMSO) δ 2.25 (s, 3H), 2.45-2.50 (m, 4H),3.37-3.43 (m, 4H), 3.75 (s, 6H), 5.08 (s, 2H), 5.88 (bs, 1H), 6.45 (t,1H), 6.60 (d, 2H), 7.45-7.49 (m, 1H), 7.94 (d, 1H), 8.35 (d, 1H), 10.89(bs, 1H), 11.36 (bs, 1H) MS: m/z 453 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.122 μM.

5-(4-Methylpiperazin-1-yl)pyridine-2-carboxylate, used as startingmaterial was prepared as follows:—

Methyl 5-bromo 2-carboxylate (250 mg, 1.16 mmol, 1 eq), potassiumphosphate (334 mg, 1.62 mmol, 1.4 eq), S-Phos (96 mg, 0.231 mmol, 0.2eq) and Pd₂dba₃ (13 mg, 0.058 mmol, 0.05 eq) were stirred in toluene (5ml) under nitrogen. N-Methylpiperazine (155 μl, 1.39 mmol, 1.2 eq) wasadded and the mixture was stirred at 100° C. for 48 h, then allowed tocool to room temperature and stirred for a further 48 h. The reactionmixture was poured onto a SCX column and washed through with MeOH, thenwith 2M NH₃ in MeOH to elute the product. Product fractions wereevaporated to afford 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate asan orange oil which crystallized on standing (194 mg, 72% yield).

¹H NMR (399.902 MHz, DMSO) δ 2.24 (s, 3H), 2.43-2.48 (m, 4H), 3.35-3.40(m, 4H), 3.81 (s, 3H), 7.32-7.37 (m, 1H), 7.88 (d, 1H), 8.38 (d, 1H).MS: m/z 236 (MH+)

tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate, used asa starting material was prepared as outlined in Example 70.

Example 70N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(2-dimethylaminoethylamino)benzamideHydrochloride

tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (150 mg,0.429 mmol) and methyl4-[2-dimethylaminoethyl-[tert-butoxycarbonyl]amino]benzoate (166 mg,0.515 mmol) were dissolved in dry THF (2.5 ml). NaHMDS (1 M in THF,0.645 ml) was added dropwise under nitrogen and the mixture was stirredfor 1 h at room temperature. The mixture was neutralised with NH₄Cl(aq), diluted with water and extracted with ethyl acetate. The extractswere combined, dried and evaporated. The crude product was purified bysilica column chromatography, eluting with a gradient of 0-8% MeOH inDCM. Pure fractions were combined and evaporated to give a brown oil (74mg). The oil was dissolved in THF (10 ml) and 4 M HCl in dioxane (2 ml)was added. The reaction mixture was stirred at room temperature for 18h. The solid was collected by filtration, washed (hexane) and dried togiveN-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(2-dimethylaminoethylamino)benzamidehydrochloride (38.6 mg, 20% overall yield) as a white solid; ¹H NMR(399.902 MHz, DMSO) δ 2.84 (d, J=4.0 Hz, 6H), 3.25 (m, 2H), 3.75 (s,6H), 5.08 (s, 2H), 5.67 (s, 1H), 6.45 (t, J=2.2 Hz, 1H), 6.60 (d, J=2.2Hz, 2H), 6.72 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 9.85 (s, 1H),10.53 (s, 1H). MS: m/z=440 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.031 μM.

tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate, used asstarting material, was prepared as follows:—

Potassium hydroxide (11.19 g, 199.4 mmol) dissolved in water (44.8 ml)was added to a solution of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (7.121 g) dissolvedin dichloromethane (40 ml). (2-Methylpropan-2-yl)oxycarbonyl tert-butylcarbonate (6.8 g, 31.2 mmol) dissolved in DCM (35 ml) was added and thereaction mixture was stirred vigorously at room temperature for 4 h. Thereaction mixture was separated and the organic layer was washed withwater (2×15 ml), brine (2×15 ml), dried over sodium sulphate, filtered,evaporated and dried in vacuo to give tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (8.70 g,99%) as a cream solid.

¹H NMR (399.902 MHz, DMSO) δ 1.55 (s, 9H), 3.75 (s, 6H), 4.93 (s, 1H),5.06 (s, 2H), 6.38 (s, 2H), 6.45 (t, J=2.2 Hz, 1H), 6.60 (d, J=2.3 Hz,2H). MS: m/z=350 (MH+)

Methyl 4-[2-dimethylaminoethyl-[tert-butoxycarbonyl]amino]benzoate, usedas starting material, was prepared as follows:—

Methyl 4-(2-[dimethylamino]ethylamino)benzoate (1.00 g, 4.50 mmol) wasdissolved in THF (30 ml). (2-Methylpropan-2-yl)oxycarbonyl tert-butylcarbonate (1.035 g, 4.72 mmol) was added and the solution was refluxedfor 3 h. The solvent was then evaporated, the residue was dissolved inDCM, washed with sat. aq. ammonium chloride solution, dried over sodiumsulphate, filtered and evaporated to give methyl4-[2-dimethylaminoethyl-[tert-butoxycarbonyl]amino]benzoate (1.07 g,74%) as a brown oil.

¹H NMR (399.902 MHz, DMSO) δ 1.41 (s, 9H), 2.13 (s, 6H), 2.34 (t, J=6.9Hz, 2H), 3.73 (t, J=6.8 Hz, 2H), 3.86 (s, 3H), 7.43 (d, J=8.5 Hz, 2H),7.94 (d, J=8.5 Hz, 2H). MS: m/z=323 (MH+)

Methyl 4-(2-[dimethylamino]ethylamino)benzoate, used as startingmaterial, was prepared as follows:—

Methyl 4-iodobenzoate (1.19 g, 4.54 mmol, 1.0 eq) was dissolved in drydimethylformamide (10 ml). N,N-dimethylethane-1,2-diamine (400 mg, 4.54mmol, 1.0 eq), caesium carbonate (2.69 g, 9.08 mmol, 2.0 eq),2-acetylcyclohexanone (120 μl, 0.908 mmol, 0.20 eq [20 mol %]) andcopper (I) iodide (44 mg, 0.227 mmol, 0.05 eq [5 mol %]) were added andthe mixture was stirred under nitrogen at 90° C. for 18 h. The reactionmixture was concentrated, dissolved in methanol and absorbed onto aSCX-2 cation exchange resin column. The column was washed with methanoland the product was eluted with 2M ammonia in methanol. Fractions wereevaporated to give methyl 4-(2-[dimethylamino]ethylamino)benzoate (1.00g, 99%) as a brown gum.

¹H NMR (399.902 MHz, DMSO) δ 2.19 (s, 6H), 2.44 (t, J=6.3 Hz, 5H), 3.17(m, 2H), 3.75 (s, 3H), 6.33 (t, J=5.3 Hz, 1H), 6.62 (d, J=8.9 Hz, 2H),7.69 (d, J=8.7 Hz, 2H). MS: m/z=223 (MH+)

Example 71N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-methoxy-benzamide

4-Methoxybenzoyl chloride (54 mg, 0.315 mmol, 1.1 eq) in THF (2 ml) wasadded dropwise to a solution of tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (100 mg,0.286 mmol, 1 eq) in THF (3 ml) under nitrogen and the solution washeated at reflux for a total of 14 h, then stirred at room temperaturefor 16 h. The solvent was evaporated and the residue was purified byprep. HPLC, using a gradient of 55-75% MeCN in H₂O (containing 1%ammonium hydroxide). The product fractions were evaporated to drynessand taken up in DCM (4 ml). 4M HCl in dioxane (1 ml) was added and themixture stirred at room temperature for 1 h, then evaporated to dryness.The residue was partitioned between ethyl acetate (6 ml) and aqueousNaHCO₃ (6 ml), the layers were separated and the aqueous layer wasre-extracted with ethyl acetate (3×6 ml). The combined organic extractswere dried over Na₂SO₄, filtered and evaporated to afford the titlecompound as an off-white solid (22 mg, 20% yield); ¹H NMR (400.132 MHz,DMSO) δ 3.74 (s, 6H), 3.82 (s, 3H), 5.06 (s, 2H), 5.59 (s, 1H), 6.43 (t,1H), 6.59 (d, 2H), 7.00 (d, 2H), 7.96 (d, 2H) MS: m/z 384 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.157 μM.

tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate, used asa starting material was prepared as outlined in Example 70.

Example 72N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-6-piperazin-1-yl-pyridine-3-carboxamide

6-[4-[(2-Methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]pyridine-3-carboxylicacid (150 mg, 0.412 mmol) was dissolved in dry THF (10 ml),1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (65 μl, 0.412 mmol) was addedand the mixture was stirred at room temperature under nitrogenovernight. Pyridine (40 μl, 0.412 mmol) and tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (142 mg,0.343 mmol) were added and the mixture was stirred at 65° C. for 18 h.The mixture was then cooled to room temperature and stirred overnightwith 4 M HCl in dioxane (1.8 ml, 7.20 mmol). The mixture was thenfiltered and the solid was washed with hexane. The product was purifiedon acidic prep. HPLC, eluting with a gradient of 16-26% MeCN in water(containing 0.1% TFA). The product containing fractions were neutralisedwith aq. NaHCO₃ and the acetonitrile removed under vacuum. The productprecipitated out and was collected by filtration. This was furtherwashed with water and dried in vacuo to give the title compound (39 mg,26%) as a white solid; ¹H NMR (399.902 MHz, DMSO) δ 2.82 (t, J=5.1 Hz,4H), 3.61 (t, J=4.8 Hz, 4H), 3.80 (s, 6H), 5.13 (s, 2H), 5.62 (bs, 1H),6.50 (s, 1H), 6.65 (d, J=2.2 Hz, 2H), 6.92 (d, J=8.9 Hz, 1H), 8.09 (d,J=9.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H), 10.74 (bs, 1H), 11.64 (bs, 1H).

MS: m/z=439 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.025 μM.

tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate, used asstarting material, was prepared as follows:

Potassium hydroxide (11.19 g, 199.4 mmol) dissolved in water (44.8 ml)was added to a solution of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (7.121 g) dissolvedin dichloromethane (40 ml). A solution of(2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (6.8 g, 31.2 mmol)in DCM (35 ml) was added and the reaction mixture was stirred vigorouslyat room temperature for 4 h. The reaction mixture was separated and theorganic layer was washed with water (2×15 ml) and brine (2×15 ml), driedover sodium sulphate, filtered, evaporated and dried in vacuo to givetert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (8.70 g,99%) as a cream solid.

¹H NMR (399.902 MHz, DMSO) δ 1.55 (s, 9H), 3.75 (s, 6H), 4.93 (s, 1H),5.06 (s, 2H), 6.38 (s, 2H), 6.45 (t, J=2.2 Hz, 1H), 6.60 (d, J=2.3 Hz,2H). MS: m/z=350 (MH+)

Example 73N-[5-[(3,5-Dimethoxyphenyl)methoxy]-1H-pyrazol-3-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide

NaHMDS (1M solution in THF, 0.39 ml, 0.386 mmol, 1.5 eq) was addeddropwise to a stirred solution of tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (90 mg,0.258 mmol, 1 eq) and methyl2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (74 mg, 0.309 mmol,1.2 eq) in dry THF (5 ml) under nitrogen. The solution was stirred atroom temperature for 1 h, then neutralised with satd. aq. NH₄Cl, dilutedwith water (15 ml) and extracted with ethyl acetate (3×15 ml). Thecombined organic extracts were dried over MgSO₄, filtered and evaporatedto give an orange gum. The gum was purified by silica columnchromatography, eluting with a gradient of 0-2.5% MeOH in DCM. The crudematerial, containing starting methyl2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate, was re-dissolved inTHF (5 ml) under nitrogen. tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (50 mg,0.143 mmol) was added followed by dropwise addition of NaHMDS (1Msolution in THF, 0.32 ml, 0.32 mmol). The solution was stirred at roomtemperature for 45 mins, neutralised with satd. aq. NH₄Cl, diluted withwater (10 ml) and extracted with ethyl acetate (3×10 ml). The combinedorganic extracts were dried over MgSO₄, filtered and evaporated. Thegummy residue was purified by silica column chromatography, eluting witha gradient of 0-8% MeOH in DCM, to afford the title compound as a palebrown solid (16 mg, 14% yield); ¹H NMR (399.9 MHz, DMSO-d₆+d4-AcOD) δ2.42 (3H, s), 2.67-2.70 (4H, m), 3.75 (6H, s), 3.91-3.94 (4H, m), 5.08(2H, s), 5.75 (1H, s), 6.45 (1H, t), 6.59 (2H, d), 8.90 (2H, s). MS: m/z454 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.044 μM.

tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate, used asa starting material was prepared as outlined in Example 70.

Methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate, used asstarting material was prepared as follows:

2-Chloropyrimidine 5-carboxylic acid (100 mg, 0.631 mmol, 1 eq) wassuspended in a mixture of toluene (3 ml) and methanol (0.8 ml) undernitrogen and cooled in an ice-bath. Trimethylsilyldiazomethane (2Msolution in hexanes, 0.347 ml, 0.694 mmol, 1.1 eq) was added dropwise.The solution was stirred at 0° C. for 10 min, then allowed to warm toroom temperature and stirred for a further 1 h. 1-Methylpiperazine (70μl, 0.631 mmol, 1 eq) and triethylamine (88 μl, 0.631 mmol, 1 eq) wereadded dropwise and stirring continued at room temperature for 2 h. Thesolvent was evaporated and the residue was taken up in ethyl acetate (20ml) and water (15 ml). The layers were separated and the aqueousextracted with further portions of ethyl acetate (2×10 ml). The combinedextracts were dried over MgSO₄, filtered and evaporated. The reactionwas repeated as above and the extracts combined with those above toafford methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate as agummy yellow solid (76 mg, 25% yield).

¹H NMR (399.902 MHz, DMSO) δ 2.12 (s, 3H), 2.27 (t, 4H), 3.70 (s, 3H),3.75 (t, 4H), 8.68 (s, 2H). MS: m/z 237 (MH+)

Example 74N-[5-[(3,5-Dimethoxyphenyl)methoxy]-1H-pyrazol-3-yl]-3-piperazin-1-yl-benzamide

1-Chloro-N,N-2-trimethyl-1-propenylamine (78 μl, 0.588 mmol, 1.2 eq) wasadded dropwise to a stirred solution of3-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoic acid (150 mg, 0.588mmol, 1.2 eq) in THF (10 ml) under nitrogen. The mixture was stirred atroom temperature overnight. tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (172 mg,0.490 mmol, 1 eq) and pyridine (48 μl, 0.588 mol, 1.2 eq) were added andthe mixture was heated at 65° C. overnight. The mixture was allowed tocool to room temperature and 4M HCl in dioxane (2 ml) was added.Stirring was continued at room temperature overnight. The precipitatedyellow solid was collected by filtration and washed with THF. The solidwas triturated with aq NaHCO₃ (4 ml) and DCM (2 ml). A small amount of abrown gum remained out of solution. The gum was collected by filtrationand washed with water and ether. The aqueous filtrate was extracted withethyl acetate (3×10 ml) and the combined extracts were dried over MgSO₄,filtered and evaporated. The extracted product was combined with the gumfrom filtration and purified by silica column chromatography, elutingwith a gradient of 10-12% MeOH in DCM. Product fractions were evaporatedto give the title compound as a white solid (27 mg, 10% yield); ¹H NMR(399.902 MHz, DMSO+d4-AcOD) δ 3.13-3.21 (m, 4H), 3.33-3.40 (m, 4H), 3.68(s, 6H), 5.02 (s, 2H), 5.71 (s, 1H), 6.38 (t, 1H), 6.52 (d, 2H),7.12-7.17 (m, 1H), 7.33 (t, 1H), 7.37-7.41 (m, 1H), 7.46-7.49 (m, 1H).MS: m/z 438 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.130 μM.

Example 754-(1,4-Diazepan-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-1H-pyrazol-3-yl]benzamideHydrochloride

tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (176 mg,0.50 mmol) and tert-butyl4-(4-methoxycarbonylphenyl)-1,4-diazepane-1-carboxylate (168 mg, 0.60mmol) were dissolved in dry THF (5 ml). NaHMDS (1 M in THF, 0.754 ml)was added dropwise under nitrogen and the mixture was stirred for 1 h atroom temperature. A further amount of NaHMDS (1M in THF, 0.754 ml) wasadded and the reaction mixture was stirred under nitrogen for 30 mins.The reaction mixture was neutralised with saturated NH₄Cl (aq), dilutedwith water (20 ml) and extracted with ethyl acetate (3×30 ml). Theextracts were combined, dried over MgSO₄, filtered and evaporated. Theresidue was purified by silica column chromatography, eluting with 0-3%MeOH in DCM. The fractions were evaporated to give a brown oil (51 mg)which was repurified by silica column chromatography, eluting with 0-1%MeOH in DCM. The pure fractions were combined, evaporated and theresidue was dissolved in THF (10 ml). 4M HCl in dioxan (1.5 ml, 1.5mmol) was added and the solution was stirred at room temperatureovernight. The precipitate was collected by filtration, washed withhexane and dried in vacuo to give the title compound (18.7 mg, 6.5%) asa white solid; ¹H NMR (399.902 MHz, DMSO) δ 2.01 (m, 2H), 3.08 (m, 2H),3.20 (m, 2H), 3.53 (m, 2H), 3.68 (s, 6H), 3.72 (t, J=5.2 Hz, 2H), 5.01(s, 2H), 5.60 (s, 1H), 6.38 (t, J=2.4 Hz, 1H), 6.52 (d, J=2.3 Hz, 2H),6.81 (d, J=9.2 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 8.69 (s, 1H), 10.49 (s,1H). MS: m/z=452 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.0085 μM.

tert-Butyl 4-(4-methoxycarbonylphenyl)-1,4-diazepane-1-carboxylate usedas starting material was prepared as follows:—

Methyl 4-iodobenzoate (1.00 g, 3.82 mmol, 1.0 eq) was dissolved in DMFand tert-butyl 1,4-diazepane-1-carboxylate (765 mg, 3.82 mmol, 1.0 eq),caesium carbonate (2.49 g, 7.63 mmol, 2.0 eq), 2-acetylcyclohexanone(101 μl, 0.76 mmol, 0.20 eq [20 mol %]) and copper iodide (37 mg, 0.19mmol, 0.05 eq [5 mol %]) were added. The reaction mixture was stirred at90° C. under nitrogen for 7 h. The reaction mixture was evaporated,dissolved in DCM (50 ml), washed with water (20 ml), saturated ammoniumchloride solution (20 ml), dried over MgSO₄, filtered and evaporated.The crude product was purified by silica column chromatography, elutingwith 0-1% MeOH in DCM. The product containing fractions were combined,evaporated and dried in vacuo to give tert-butyl4-(4-methoxycarbonylphenyl)-1,4-diazepane-1-carboxylate (168 mg, 13%) asa yellow oil.

¹H NMR (399.902 MHz, DMSO) δ 1.12 (s, 5H), 1.24 (s, 4H), 1.72 (m, 2H),3.12 (m, 1H), 3.42 (m, 1H), 3.49 (m, 3H), 3.59 (m, 2H), 3.69 (s, 3H),6.72 (d, J=9.1 Hz, 2H), 7.67 (d, J=9.0 Hz, 2H) MS: m/z=335 (MH+)

tert-Butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate wasprepared as follows:

Potassium hydroxide (11.19 g, 199.4 mmol) dissolved in water (44.8 ml)was added to a solution of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (7.121 g) dissolvedin dichloromethane (40 ml). (2-Methylpropan-2-yl)oxycarbonyl tert-butylcarbonate (6.8 g, 31.2 mmol) dissolved in DCM (35 ml) was added and thereaction mixture was stirred vigorously at room temperature for 4 h. Thereaction mixture was separated and the organic layer was washed withwater (2×15 ml) and brine (2×15 ml), dried over sodium sulphate,filtered, evaporated and dried in vacuo to give tert-butyl5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (8.70 g,99%) as a cream solid.

¹H NMR (399.902 MHz, DMSO) δ 1.55 (s, 9H), 3.75 (s, 6H), 4.93 (s, 1H),5.06 (s, 2H), 6.38 (s, 2H), 6.45 (t, J=2.2 Hz, 1H), 6.60 (d, J=2.3 Hz,2H). MS: m/z=350 (MH+)

Example 76N-[5-[2-[5-(Dimethylaminomethyl)-2-furyl]ethyl]-1H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

A solution of potassium hydroxide (4.5M in water, 1.8 ml, 8.10 mmol,8.10 eq) was added to a stirred solution of5-(2-{5-[(dimethylamino)methyl]-2-furyl}ethyl)-1H-pyrazol-3-amine (235mg, 1.0 mmol, 1.0 eq) in dichloromethane at room temperature. A solutionof di-tert-butyl dicarbonate (230 mg, 1.05 mmol, 1.05 eq) indichloromethane (2.0 ml) was then added and the reaction mixture stirredvigorously for 18 h. The reaction mixture was poured into a separatingfunnel and the layers were separated. The dichloromethane layer waswashed with water (10 ml) and saturated brine (10 ml), dried overanhydrous sodium sulphate, filtered and the solvent removed in vacuo toafford tert-butyl5-amino-3-(2-{5-[(dimethylamino)methyl]-2-furyl}ethyl)-1H-pyrazole-1-carboxylateas a golden oil, (320 mg).

A portion of this material was used without further purification asfollows:—

A solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran,0.7 ml, 0.69 mmol, 1.50 eq) was added dropwise at room temperature to astirred solution of tert-butyl5-amino-3-(2-{5-[(dimethylamino)methyl]-2-furyl}ethyl)-1H-pyrazole-1-carboxylate(crude 154 mg, 0.46 mmol, 1.0 eq) and methyl4-(4-methylpiperazin-1-yl)benzoate (130 mg, 0.55 mmol, 1.20 eq) in drytetrahydrofuran (1.0 ml) under nitrogen. The mixture was allowed tostand at room temperature overnight and then the solvent was evaporatedunder reduced pressure to afford the crude product as a brown gum. Thisgum was dissolved in methanol (5 ml) and the solution was applied to aSCX-2 column. The column was washed through with methanol containing 10%water. The column was then eluted with 2.0M anhydrous ammonia inmethanol. Fractions containing the product were combined and evaporatedto give a brown gum, 235 mg. This material was further purified bysilica column chromatography, eluting with a 3-10% gradient of methanol(containing ammonia at 2M) in dichloromethane. Pure product fractionswere combined and evaporated to give a light brown gum, 32.9 mg. Thismaterial was further purified by reverse-phase prep. HPLC (basic) usinga 30-50% gradient of acetonitrile in water containing 1% ammoniumhydroxide solution. The clean fractions were taken and evaporated toafford the title compound as a solid. (8 mg, 4% yield); ¹H NMR (500.13MHz, DMSO-d6) δ 2.17 (6H, d), 2.26 (3H, s), 2.48 (4H, t), 2.88-2.96 (4H,m), 3.30 (4H, t), 3.39 (2H, s), 6.03 (1H, d), 6.12 (1H, d), 6.95 (2H,d), 7.88 (2H, d), 9.95 (1H, broad s), 11.80 (1H, broad s). MS: m/z 437(MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.34 μM.

5-(2-{5-[(dimethylamino)methyl]-2-furyl}ethyl)-1H-pyrazol-3-amine, usedas starting material was prepared as follows:

Acetonitrile (0.258 ml, 4.88 mmol) was added to a slurry of sodiumhydride (196 mg dispersion in mineral oil, 4.88 mmol) in anhydrousdioxan (15 ml) and the mixture stirred at room temperature under anatmosphere of nitrogen for 5 mins. Ethyl3-{5-[(dimethylamino)methyl]-2-furyl}propanoate (917 mg, 4.07 mmol) wasthen added and the reaction was refluxed for 18 h. The mixture wascooled to room temperature and ethanol (1.9 ml) added followed byhydrazine hydrochloride (558 mg, 8.14 mmol). The mixture was refluxedfor 1 h. After cooling, the solvent was evaporated under reducedpressure. The residue was dissolved in dichloromethane containing 10%methanol (50 mL) and the insoluble impurities were filtered off. Thefiltrate was evaporated to give the crude product as a golden oil, 1.07g. This material was purified by silica column chromatography, elutingwith a 0-10% gradient of methanol (containing ammonia at 2M) indichloromethane. Pure product fractions were combined and evaporated togive a clear oil. (520 mg, 55% yield); ¹H NMR (399.9 MHz, DMSO-d6) δ2.16(6H, s), 2.70-2.74 (2H, m), 2.81-2.85 (2H, m), 3.40 (2H, s), 5.20 (1H,s), 6.03 (1H, d), 6.15 (1H, d). MS: m/z 235 (MH+)

Ethyl 3-{5-[(dimethylamino)methyl]-2-furyl}propanoate, used as startingmaterial was prepared as follows:

A mixture of ethyl 3-(2-furanyl)propionate (12.11 g, 72.0 mmol),dimethylammonium chloride (6.76 g, 82.8 mmol), 37% aqueous formaldehyde(6.43 g, 79.2 mmol) in acetic acid (75 ml) was stirred at roomtemperature until a solution formed. The solution was allowed to standfor 44 h. The mixture was evaporated to an oil. This was suspended inwater and extracted with ethyl acetate (2×250 ml). The aqueous layer(containing the product) was basified to pH11 with 4M sodium hydroxidesolution and then extracted into ethyl acetate (2×250 ml). Thesecombined extracts were washed with brine, dried over magnesium sulphateand evaporated to give the crude product as a dark brown oil, 6.5 g.This material was purified by silica column chromatography, eluting witha 0-10% gradient of methanol (containing ammonia at 2M) indichloromethane. Fractions containing the product were combined andevaporated to give a light brown oil (3.44 g). This material waspurified by silica column chromatography, eluting with a 0-5% gradientof methanol (containing ammonia at 2M) in dichloromethane. Fractionscontaining the product were combined and evaporated to give a lightbrown oil (1.36 g, 8% yield).

1H NMR (399.9 MHz, CDCl3) δ 1.24 (3H, t), 2.29 (6H, s), 2.62-2.65 (2H,m), 2.95 (2H, t), 3.47 (2H, s), 4.11-4.15 (2H, m), 5.95 (1H, d), 6.11(1H, d). MS: m/z 226 (MH+)

Example 77N-[5-(2-Benzo[1,3]dioxol-5-ylethyl)-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

To a stirred solution of tert-butyl5-amino-3-(2-benzo[1,3]dioxol-5-ylethyl)pyrazole-1-carboxylate (229 mg,0.69 mmol, 1.0 eq) in pyridine (5 ml) at 5° C. was added4-(4-methylpiperazin-1-yl)benzoyl chloride (181 mg, 0.76 mmol, 1.1 eq).The reaction mixture was stirred to 60° C. for 24 h. After this time,the mixture was concentrated and redissolved in DCM (10 ml).Trifluoroacetic acid (464 μl, 6.25 mmol, 8.25 eq) was added and thereaction mixture stirred for 2 h at 25° C. The reaction mixture was thenconcentrated. The crude product was purified by reverse-phase prep. HPLC(basic) using a 30-50% gradient of acetonitrile in water containing 1%ammonium hydroxide solution. The clean fractions were combined andevaporated to afford the title compound as a white solid. (12 mg, 4%);¹H NMR (300.132 MHz, DMSO) δ 2.28 (s, 3H), 2.49 (t, 2H), 2.89 (s, 2H),3.31-3.37 (m, 8H), 6.01 (s, 2H), 6.43 (s, 1H), 6.74 (d, 1H), 6.86 (d,2H), 7.01 (d, 2H), 7.94 (d, 2H), 10.36 (s, 1H), 12.11 (s, 1H); MS: m/z434 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.14 μM.

tert-butyl5-amino-3-(2-benzo[1,3]dioxol-5-ylethyl)pyrazole-1-carboxylate, used asstarting material was prepared as follows:

To a stirred solution of5-(2-benzo[1,3]dioxol-5-ylethyl)-2H-pyrazol-3-amine in DCM (10 ml) wasadded 4.5M aq. KOH solution (1.9 ml, 8.66 mmol, 8 eq). A solution ofBOC₂O (464 mg, 2.12 mmol, 1.05 eq) in DCM (2 mL) was then added and thereaction mixture stirred vigorously for 3 h. The reaction mixture waspoured into a separating funnel and the layers separated. The organiclayer was washed with water (10 mL), brine (10 mL), dried (Na₂SO₄),filtered and the solvent evaporated to afford the title compound as awhite solid. (325 mg, 91%); ¹H NMR (300.132 MHz, DMSO) δ 1.55 (s, 9H),2.58-2.64 (m, 2H), 2.73-2.78 (m, 2H), 5.19 (s, 1H), 5.95 (s, 2H), 6.21(s, 2H), 6.68-6.71 (m, 1H), 6.80 (d, 1H), 6.85 (d, 1H)

5-(2-benzo[1,3]dioxol-5-ylethyl)-2H-pyrazol-3-amine, used as startingmaterial was prepared as follows:—

5-(2-Benzo[1,3]dioxol-5-ylethyl)-2H-pyrazol-3-amine used as startingmaterial was prepared in a similar manner to5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-amine in example 11. Productwas obtained as yellow oil. (3.04 g, 44% yield).

1H NMR (300.132 MHz, DMSO): δ 2.63-2.79 (m, 4H), 4.40 (s, 2H), 5.18 (s,1H), 5.95 (s, 2H), 6.66 (dd, 1H), 6.77-6.81 (m, 2H). MS: m/z 232 (MH+).

Example 78N-[5-[2-(2,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

Made in an analogous way to the compound in example 77, using tert-butyl5-amino-3-[2-(2,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (240 mg,0.69 mmol, 1 eq) as starting material to afford the title compound as awhite solid. (27 mg, 9%);

¹H NMR (300.132 MHz, DMSO) δ 2.23 (s, 3H), 2.43-2.46 (m, 4H), 2.80-2.88(m, 4H), 3.26-3.29 (m, 4H), 3.68 (s, 3H), 3.76 (s, 3H), 6.43 (s, 1H),6.72-6.77 (m, 2H), 6.88 (d, 1H), 6.96 (d, 2H), 7.89 (d, 2H), 10.29 (s,1H), 12.06 (s, 1H)

MS: m/z 450 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.47 μM.

tert-butyl5-amino-3-[2-(2,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate, used asstarting material was made in an analogous way to tert-butyl5-amino-3-(2-benzo[1,3]dioxol-5-ylethyl)pyrazole-1-carboxylate inExample 77, using 5-[2-(2,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine(200 mg, 0.87 mmol, 1 eq) as starting material to afford the titlecompound as a white solid. (283 mg, 94%).

1H NMR (300.132 MHz, DMSO) δ 1.60 (s, 9H), 2.61-2.67 (m, 2H), 2.79-2.84(m, 2H), 3.73 (s, 3H), 3.79 (s, 3H), 5.25 (s, 1H), 6.26 (s, 2H),6.75-6.79 (m, 1H), 6.84 (d, 1H), 6.92 (d, 1H)

5-[2-(2,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial, was prepared as follows:—

Sodium hydride (60%, 0.240 g, 6 mmol) was added to a stirred solution ofmethyl 3-(2,5-dimethoxyphenyl)propanoate (1.125 g, 5 mmol) in 1,4dioxane (25 ml) in dry acetonitrile (0.314 ml, 6 mmol) under nitrogen.The mixture was stirred at r.t for 10 mins then heated at reflux undernitrogen for 18 h. After this time, the mixture was cooled to r.t. uponwhich a precipitate formed. Ethanol (2 ml) was added, followed byhydrazine monohydrochloride (0.686 g, 10 mmol). The mixture was heatedto reflux for 4 h. In this time, the precipitate went into solution anda solid appeared. After filtration, the reaction mixture wasconcentrated in vacuo and partitioned between 2N HCl and ethyl acetate(25 ml each). The aqueous layer was basified with ammonium hydroxidesolution to pH 8, extracted with ethyl acetate and dried with MgSO₄.This was filtered, and the solvents were evaporated in vacuo to give anorange oil (0.690 g, 56%).

4-(4-Methylpiperazin-1-yl)benzoyl chloride, used as starting materialwas prepared as per Example 61.

Example 79N-[5-[2-(4-Methoxy-2-methyl-phenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

Made in an analogous way to the compound in example 77, using tert-butyl5-amino-3-[2-(4-methoxy-2-methyl-phenyl)ethyl]pyrazole-1-carboxylate(229 mg, 0.69 mmol, 1 eq) as starting material to afford the titlecompound as a white solid. (15 mg, 5%); ¹H NMR (300.132 MHz, DMSO) δ2.26 (s, 3H), 2.72-2.83 (m, 5H), 2.88 (t, 4H), 3.41 (t, 4H), 3.69 (s,3H), 5.70 (s, 1H), 6.41 (s, 1H), 6.65-6.73 (m, 2H), 6.99 (d, 2H), 7.06(d, 1H), 7.91 (d, 2H) [NB: With D4-Acetic added]

MS: m/z 434 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.2 μM.

tert-butyl5-amino-3-[2-(4-methoxy-2-methyl-phenyl)ethyl]pyrazole-1-carboxylate,used as starting material was made in an analogous way to tert-butyl5-amino-3-(2-benzo[1,3]dioxol-5-ylethyl)pyrazole-1-carboxylate inExample 77, using5-[2-(4-methoxy-2-methyl-phenyl)ethyl]-2H-pyrazol-3-amine (214 mg, 0.87mmol, 1 eq) as starting material to afford the title compound as a whitesolid. (256 mg, 89%).

1H NMR (300.132 MHz, DMSO) δ 1.60 (s, 9H), 2.30 (s, 3H), 2.58-2.64 (m,2H), 2.76-2.81 (m, 2H), 3.75 (s, 3H), 5.26 (s, 1H), 6.26 (s, 2H),6.70-6.74 (m, 1H), 6.77 (d, 1H), 7.13 (d, 1H)

5-[2-(4-methoxy-2-methyl-phenyl)ethyl]-2H-pyrazol-3-amine, used asstarting material was prepared as follows:—

5-[2-(4-methoxy-2-methyl-phenyl)ethyl]-2H-pyrazol-3-amine, used asstarting material, was prepared in a method analogous to that used tosynthesize 5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-amine in example 11using methyl 3-(4-methoxy-2-methyl-phenyl)propanoate as startingmaterial to give5-[2-(4-methoxy-2-methyl-phenyl)ethyl]-2H-pyrazol-3-amine as a redsolid. MS: m/z 232 (MH+).

4-(4-Methylpiperazin-1-yl)benzoyl chloride, used as starting materialwas prepared as per example 61.

Example 80N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamidewas prepared as for Example 94, but starting from methyl4-(3,5-dimethylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (basic) using a34-54% gradient of acetonitrile in water containing 1% 0.880 ammonia.The clean fractions were taken and evaporated to afford the titlecompound as a white solid (34 mg, 10%); ¹H NMR (399.9 MHz, DMSO-d₆) δ1.04 (6H, d), 2.22 (2H, t), 2.53 (2H, d), 2.82 (2H, t), 2.87 (4H, s),3.71 (1H, s), 3.73 (7H, s), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s),6.94 (2H, d), 7.89 (2H, d), 10.27 (1H, s), 12.07 (1H, s).

MS: m/z 464 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.011 μM.

2,6-Dimethylpiperazine (3.43 g, 30.00 mmol) was added to ethyl4-fluorobenzoate (1.101 mL, 7.5 mmol), in DMSO (10 mL) warmed to 120° C.under nitrogen. The resulting solution was stirred at 120° C. for 20 h.The reaction mixture was cooled and the solvent was evaporated. Thecrude product was purified by silica column chromatography, eluting with10% methanol in dichloromethane containing 1% 0.880 ammonia. Purefractions were evaporated to dryness to afford ethyl4-(3,5-dimethylpiperazin-1-yl)benzoate (1.490 g, 76%) as a colourlesssolid.

1H NMR (399.9 MHz, CDCl₃) δ 1.15 (6H, d), 1.37 (3H, t), 2.39 (1H, d),2.42 (1H, d), 2.97-3.05 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q),6.84-6.87 (2H, m), 7.90-7.93 (2H, m)—NH not seen. MS: m/z=264 (MH+).

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 81N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamidewas prepared as for Example 94, but starting from methyl4-(3,4-dimethylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (basic) using a38-58% gradient of acetonitrile in water containing 1% 0.880 ammoniumhydroxide. The clean fractions were taken and evaporated to afford thetitle compound as a white solid (63 mg, 19%); ¹H NMR (500.13 MHz,DMSO-d₆) δ 1.12 (3H, d), 1.89-1.90 (3H, m), 2.32 (3H, s), 2.35-2.40 (1H,m), 2.64-2.68 (1H, m), 2.86-2.91 (1H, m), 2.89 (4H, t), 3.00 (1H, s),3.64-3.68 (2H, m), 3.74 (6H, s), 6.32 (1H, s), 6.33 (1H, t), 6.42 (2H,d), 6.94-6.96 (2H, m), 7.86-7.88 (2H, m). MS: m/z 464 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.04 μM.

1,2-Dimethyl-piperazine (0.914 g, 8.00 mmol) and ethyl 4-fluorobenzoate(0.587 mL, 4 mmol) were dissolved in DMA (6 mL) and sealed into amicrowave tube. The reaction was heated to 150° C. for 90 mins in themicrowave reactor and cooled to room temperature. The reaction mixturewas evaporated and the crude product was purified by silica columnchromatography, eluting with 5% MeOH in DCM (containing 0.1% 0.880ammonia). Pure fractions were evaporated to dryness to afford ethyl4-(3,4-dimethylpiperazin-1-yl)benzoate (0.380 g, 36.2%) as a colourlesswaxy solid.

1H NMR (399.9 MHz, CDCl₃) δ 1.15 (3H, d), 1.37 (3H, t), 2.20-2.25 (1H,m), 2.34 (3H, s), 2.37-2.41 (1H, m), 2.61-2.67 (1H, m), 2.87-2.92 (1H,m), 2.99-3.06 (1H, m), 3.58-3.62 (1H, m), 3.65-3.70 (1H, m), 4.33 (2H,q), 6.83-6.87 (2H, m), 7.90-7.94 (2H, m). MS: m/z=263 (MH+).

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 82N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-iodo-benzamide

Trifluoroacetic acid (3.85 mL, 50.02 mmol) was added in one portion totert-butyl3-(3,5-dimethoxyphenethyl)-5-(4-iodobenzamido)-1H-pyrazole-1-carboxylate(288 mg, 0.5 mmol) in DCM (10 mL) at room temperature. The resultingsolution was stirred for 24 h. The reaction mixture was evaporated todryness and redissolved in MeOH (5 mL). The crude product was purifiedby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 3.5M NH3/Methanol and pure fractionswere evaporated to dryness to afford a tan solid. The solid wastriturated with DCM to give the title compound (58.0 mg, 24.3%) as awhite solid; ¹H NMR (399.9 MHz, DMSO-d6) δ 2.88 (4H, s), 3.73 (6H, s),6.33 (1H, t), 6.42 (2H, d), 6.47 (1H, s), 7.77 (2H, d), 7.87 (2H, d),10.73 (1H, s), 12.17 (1H, s).

MS m/z: 478 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.021 μM.

Tert-butyl3-(3,5-dimethoxyphenethyl)-5-(4-iodobenzamido)-1H-pyrazole-1-carboxylateused as starting material was prepared as follows:

4-Iodobenzoyl chloride (1.332 g, 5.00 mmol) was added to tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate(1.737 g, 5 mmol) and pyridine (0.445 mL, 5.50 mmol) in DCM (15 mL). Theresulting suspension was stirred at 25° C. for 24 h. The reactionmixture was evaporated to dryness and redissolved in EtOAc (25 mL), andwashed sequentially with water (10 mL) and saturated brine (10 mL). Theorganic layer was dried over MgSO₄, filtered and evaporated to affordcrude product.

The crude product was purified by silica column chromatography, elutingwith a gradient of 5-20% EtOAc in isohexane. Pure fractions wereevaporated to dryness to afford tert-butyl3-(3,5-dimethoxyphenethyl)-5-(4-iodobenzamido)-1H-pyrazole-1-carboxylate(1.187 g, 41.1%) as a white solid. 1H NMR (399.9 MHz, CDCl3) δ 1.70 (9H,s), 2.95 (4H, s), 3.78 (6H, s), 6.32 (1H, t), 6.42 (2H, d), 6.91 (1H,s), 7.64-7.67 (2H, m), 7.88-7.90 (2H, m), 11.13 (1H, s). MS m/z: 478(MH+).

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 83N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-2-[(3-methyl-1,2-oxazol-5-yl)methylamino]benzamide

NaHMDS (1M solution in THF, 0.83 ml, 0.828 mmol, 2.5 eq) was addeddropwise to a solution of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (90mg, 0.364 mmol, 1.1 eq) and methyl2-{[(3-methylisoxazol-5-yl)methyl]amino}-benzoate (115 mg, 0.331 mmol, 1eq), stirred in THF (4 ml) under nitrogen. The solution was stirred atroom temperature for 50 mins. The solution was quenched with satd. aq.NH₄Cl, diluted with water (5 ml) and extracted with ethyl acetate (3×8ml). The crude product was purified by silica column chromatography,eluting with a gradient of 0-1.5% MeOH in DCM. Fractions containingproduct were evaporated and further purified by reverse phase prep. HPLCpurification, eluting with a gradient of MeCN/H₂O+0.1% TFA to afford thetitle compound as an off-white solid (16 mg, 10% yield); ¹H NMR (399.902MHz, DMSO) δ 2.20 (s, 3H), 2.88 (s, 4H), 3.73 (s, 6H), 4.57 (s, 2H),6.21 (s, 1H), 6.33 (t, 1H), 6.41 (bs, 1H), 6.43 (d, 3H), 6.65 (t, 1H),6.77 (d, 1H), 7.28-7.34 (m, 1H), 7.75-7.79 (m, 1H), 8.10 (bs, 1H), 10.50(s, 1H). MS: m/z 462 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 1.0 μM.

Methyl 2-{[(3-methylisoxazol-5-yl)methyl]amino}-benzoate, used asstarting material was prepared as follows:

1-(3-Methylisoxazol-5-yl)methanamine (155 mg, 1.37 mmol, 1.2 eq),potassium phosphate (341 mg, 1.60 mmol, 1.4 eq), S-Phos (95 mg, 0.230mmol, 0.2 eq) and Pd₂dba₃ (13 mg, 0.06 mmol, 0.05 eq) were stirred intoluene (5 ml) under nitrogen. Methyl 2-iodobenzoate (300 mg, 1.14 mmol,1 eq) was added and the mixture was stirred at room temperature for 3days, then at 90° C. for 6 h. The reaction mixture was allowed to cool,poured into water (100 ml) and extracted with ethyl acetate (3×60 ml).The combined extracts were washed with brine, dried over MgSO₄, filteredand evaporated. The residual gummy oil was triturated with etherresulting in precipitation of a small amount of a yellow solid which wasfiltered off. The filtrate was evaporated and triturated again withmethanol and a second precipitate was removed by filtration. Thefiltrate was evaporated, then purified by silica column chromatography,eluting with DCM. The product fractions were evaporated to afford methyl2-{[(3-methylisoxazol-5-yl)methyl]amino}-benzoate as a yellow oily gum(128 mg, 45% yield); ¹H NMR (399.902 MHz, CDCl₃) δ 2.25 (s, 3H), 3.88(s, 3H), 4.53 (d, 2H), 5.99 (s, 1H), 6.62-6.70 (m, 2H), 7.32-7.38 (m,1H), 7.92-7.96 (m, 1H), 8.19 (t, 1H). MS: m/z 247 (MH+)

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 84N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide

A solution of NaHMDS (1.500 ml, 1.50 mmol) in THF (1.0M) was added to astirred solution of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate(0.347 g, 1.0 mmol) and methyl6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylate (0.284 g, 1.20 mmol)in THF (5.00 ml) cooled to 0° C. under nitrogen.

The resulting solution was stirred at ambient temperature for 70 mins.The mixture was then partitioned between ethyl acetate and saturatedaqueous ammonium chloride solution diluted with water (1:2). A solid wasfiltered off to give crude product as a white solid. This was purifiedby preparative LCMS using decreasingly polar mixtures of water(containing 0.1% TFA) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(0.127 g, 28.1%) as a white solid; ¹H NMR (500.13 MHz, DMSO-d₆, CD₃CO₂D)δ 2.69 (3H, s), 2.89-2.95 (4H, m), 3.07-3.08 (4H, m), 3.75 (6H, s),3.92-3.97 (4H, m), 6.34 (1H, s), 6.42 (3H, s), 7.41 (1H, d), 8.00 (1H,d)

MS: m/z 452 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.39 μM.

Methyl 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylate, used asstarting material was prepared as follows:—

A suspension of 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (221mg, 1.00 mmol) in sodium hydroxide (2.0M aqueous) (10.000 mL, 20.00mmol), was stirred at reflux for 3 h and then allowed to cool to roomtemperature. The reaction mixture was adjusted to pH7 by addition of 2MHCl (10 mL) and saturated NaHCO₃. The crude product was purified by ionexchange chromatography, using a SCX2 column. The desired product waseluted from the column using methanol and the fractions were evaporatedto dryness to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylicacid as a white solid. This material was suspended in methanol (10.00ml) at 0° C. and treated with thionyl chloride (0.729 ml, 10.00 mmol),over a period of 5 mins. The resulting suspension was stirred at ambienttemperature for 18 h. Sodium bicarbonate solution was added until basicand then the mixture was extracted with ethyl acetate (2×75 mL). Thesolution was further extracted with 1-butanol (100 mL). The organicextracts were combined and evaporated to dryness to give methyl6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylate a white solid, 212mg.

1H NMR (399.9 MHz, DMSO-d₆) δ 2.24 (3H, s), 2.43 (4H, t), 3.74 (4H, t),3.88 (3H, s), 7.30 (1H, d), 7.84 (1H, d)

MS: m/z 237 (MH+)

6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide, used as startingmaterial was prepared as follows:

6-Chloropyridazine-3-carboxamide (0.315 g, 2 mmol) and1-methylpiperazine (0.555 ml, 5.00 mmol) were suspended in 2-propanol(2.000 ml) and sealed into a microwave tube. The reaction was heated to130° C. for 30 mins in the microwave reactor and cooled to ambienttemperature. The resulting precipitate was collected by filtration,washed with 2-propanol (10 mL) and dried under vacuum to afford6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (0.333 g, 75%) as awhite solid, which was used without further purification. A sample (100mg) of the crude product was purified by preparative LCMS usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (54mg) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 2.24 (3H, s), 2.44 (4H, t), 3.71 (4H, t),7.34 (1H, d), 7.50 (1H, s), 7.84 (1H, d), 8.11 (1H, s)

MS: m/z 222 (MH+)

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 85N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide

A solution of NaHMDS (2.100 ml, 2.10 mmol) in THF (1.0 M) was added to astirred solution of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate(0.486 g, 1.4 mmol) and methyl2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.397 g, 1.68 mmol)in THF (7.00 ml, cooled to −20° C.), over a period of 5 mins undernitrogen. The resulting solution was stirred at room temperature for 18h. The mixture was heated to reflux for 90 min, then cooled to roomtemperature. More NaHMDS (2.100 ml, 2.10 mmol) was added and the mixturestirred for 70 mins. The mixture was allowed to stand for 96 h and thenpartitioned between ethyl acetate and 2.0M aqueous hydrochloric acid.The aqueous layer was separated and basified with 50% aqueous sodiumhydroxide solution and then extracted with ethyl acetate (75 mL). Theorganic layer was washed with saturated brine (50 mL) and then driedover MgSO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by preparative LCMS using decreasingly polarmixtures of water (containing 1% ammonia) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (4.00 mg, 0.633%) as a white solid;

¹H NMR (500.13 MHz, DMSO-d₆, CD₃CO₂D) δ 2.34 (3H, s), 2.53 (4H, t), 2.90(4H, t), 3.74 (6H, s), 3.89 (4H, t), 6.33 (1H, t), 6.35 (1H, s), 6.42(2H, d), 8.89 (2H, s)

MS: m/z 452 (MH+)

FGFR Kinase assay—Caliper, IC₅₀ 0.118 μM.

FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0149 μM.

Methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate, used asstarting material was prepared as follows:

Methyl 2-chloropyrimidine-5-carboxylate (0.863 g, 5.0 mmol),N,N-diethylethanamine (0.697 ml, 5.00 mmol) and 1-methylpiperazine(0.565 ml, 5.09 mmol) were suspended in 2-propanol (10.00 ml) and sealedinto a microwave tube. The reaction was heated to 100° C. for 10 mins inthe microwave reactor and cooled to room temperature. The precipitatewas collected by filtration, washed with EtOH (5 mL) and dried undervacuum to afford methyl2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.405 g, 34.3%) as awhite solid, which was used without further purification.

MS: m/z 237 (MH+)

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 86N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-methylpiperazine-1-carbonyl)benzamide

A solution of NaHMDS (1M in THF) (2.86 mL, 2.86 mmol) was added dropwiseto a stirred solution of methyl4-(4-methylpiperazine-1-carbonyl)benzoate (0.250 g, 0.95 mmol) andtert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate(0.397 g, 1.14 mmol) in THF (2 mL), over a period of 10 mins undernitrogen. The resulting solution was stirred at room temperature for 18h. The reaction mixture was poured into saturated NH₄Cl (25 mL),extracted with EtOAc (2×25 mL), washed with saturated brine and driedover MgSO₄, filtered and evaporated to afford the crude product (0.501g) as a yellow gum. The crude product was purified by preparative HPLCusing decreasingly polar mixtures of water (containing 1% ammoniumhydroxide) and MeCN as eluents. Fractions containing the desiredcompound were evaporated to dryness to afford the title compound (0.257g, 56.5%) as a yellow solid; ¹H NMR (399.9 MHz, DMSO-d₆) δ 2.21 (3H, s),2.25-2.40 (4H, m), 2.89 (4H, s), 3.16-3.20 (1H, d), 3.32 (4H, s), 3.72(6H, d), 6.33 (1H, m), 6.42-6.44 (2H, d), 7.46-7.50 (2H, d), 8.02-8.06(2H, d)

MS: m/z 478 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.096 μM.

Methyl 4-(4-methylpiperazine-1-carbonyl)benzoate, used as startingmaterial was prepared as follows:

Oxalyl chloride (0.533 mL, 6.11 mmol) was added dropwise to a stirredsuspension of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in DCM(20 mL) under nitrogen. The resulting suspension was stirred at roomtemperature for 30 mins. DMF (0.05 mL) was added dropwise undernitrogen. The resulting suspension was stirred for 90 mins. A solutionof 1-methylpiperazine (0.554 mL, 5.00 mmol) and pyridine (1.211 mL,14.99 mmol) in DCM (15 mL) was added dropwise at 0° C., over a period of60 mins under nitrogen. The resulting solution was stirred at roomtemperature for 3 h. The reaction mixture was evaporated to dryness toafford the crude product (1.791 g) as a dark orange solid. The solid wasredissolved in DCM and washed with NaHCO₃. The organic layer wasevaporated to dryness to afford methyl4-(4-methylpiperazine-1-carbonyl)benzoate (0.890 g, 61.1%) as an orangegum, which solidified on standing. Used without further purification.

1H NMR (399.9 MHz, CDCl3) δ 2.78 (4H, s), 3.43 (4H, s), 7.42-7.45 (2H,m), 8.04-8.06 (2H, m)

MS: m/z 263 (MH+)

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 87N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-propan-2-ylpiperazin-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-ylpiperazin-1-yl)benzamidewas prepared as for Example 94, but starting from methyl4-(4-propan-2-yl-piperizin-1-yl)benzoate (263 mg, 0.84 mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (basic) using a38-58% gradient of acetonitrile in water containing 1% 0.880 ammonia.The clean fractions were taken and evaporated to afford the titlecompound as a white solid (18 mg, 5%); ¹H NMR (399.9 MHz, DMSO-d₆) δ1.02 (6H, d), 2.55-2.61 (4H, m), 2.65-2.76 (1H, m), 2.89 (2H, s),3.21-3.28 (4H, s), 3.31 (2H, s), 3.72 (6H, s), 6.33 (1H, t), 6.42 (2H,d), 6.45 (1H, s), 6.95 (2H, d), 7.90 (2H, d), 10.29 (1H, s), 12.07 (1H,s)

MS: m/z 478 (MH+).

Mean of n=5, FGFR Kinase assay—Caliper, IC₅₀ 0.0004 μM.

Methyl 4-(4-propan-2-yl-piperizin-1-yl)benzoate used as startingmaterial was prepared as follows:—

Tris(dibenzylideneacetone)dipalladium(0) (0.014 g, 0.02 mmol) was addedto a deoxygenated suspension of 1-isopropylpiperazine (0.151 g, 1.18mmol), methyl 4-bromobenzoate (0.215 g, 1 mmol), potassium carbonate(0.193 g, 1.4 mmol) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.012 g, 0.03mmol) in DME (4 mL), and sealed into a microwave tube. The reaction washeated to 130° C. for 10 mins in the microwave reactor and cooled toroom temperature. The reaction mixture was evaporated to dryness,redissolved in EtOAc (25 mL) and washed sequentially with water (15 mL)and saturated brine (15 mL). The organic layer was dried over MgSO₄,filtered and evaporated to afford crude product. The crude product waspurified by silica column chromatography, eluting with 5% MeOH in DCM.Pure fractions were evaporated to dryness to afford methyl4-(4-propan-2-yl-piperizin-1-yl)benzoate (0.170 g, 64.8%) as a tansolid.

1H NMR (399.9 MHz, CDCl3) δ 1.09 (6H, d), 2.66 (4H, t), 2.73 (1H, q),3.34 (4H, t), 3.86 (3H, s), 6.84-6.88 (2H, m), 7.89-7.93 (2H, m). MS:m/z 264 (MH+).

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 884-(4-Cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide

4-(4-cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamidewas prepared as for Example 94, but starting from ethyl4-(4-cyclopropylpiperazin-1-yl)benzoate (193 mg, 0.7 mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (acidic) using a16-36% gradient of acetonitrile in water containing 0.1% TFA. The cleanfractions were neutralised and evaporated to afford the title compoundas a white solid (40 mg, 12%); ¹H NMR (500.13 MHz, DMSO-d₆+d₄ AceticAcid) δ 0.46 (2H, d), 0.50 (2H, d), 1.79-1.84 (1H, m), 2.78 (4H, t),2.90 (4H, s), 3.24-3.31 (4H, m), 3.75 (6H, s), 6.32 (1H, s), 6.33 (1H,t), 6.42 (2H, d), 6.94-6.96 (2H, m), 7.86-7.88 (2H, m).

FGFR Kinase assay—Caliper, IC₅₀ 0.156 μM.

FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00077 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Ethyl 4-(4-cyclopropylpiperazin-1-yl)benzoate used as starting materialwas prepared as follows:—

Ethyl 4-fluorobenzoate (0.153 mL, 1.04 mmol) and 1-cyclopropylpiperazine(0.2637 g, 2.09 mmol) were taken up in DMA (2 mL) and sealed into amicrowave tube. The reaction was heated to 150° C. for 90 mins in themicrowave reactor and cooled to room temperature. The reaction mixturewas evaporated to afford a brown gum, which solidified on standing. Thecrude product was purified by silica column chromatography, eluting with10% MeOH (containing 0.1% aqueous ammonia) in DCM. Pure fractions wereevaporated to dryness to afford the impure product as a yellow solid.The impure product was purified again by silica column chromatography,eluting with a gradient of 0-2.5% MeOH in DCM. Pure fractions wereevaporated to dryness to afford ethyl4-(4-cyclopropylpiperazin-1-yl)benzoate (0.096 g, 33.6%) as a beigesolid.

1H NMR (399.9 MHz, CDCl3) δ 0.45-0.52 (5H, m), 1.36 (3H, t), 2.75 (4H,t), 3.29 (4H, t), 4.32 (2H, q), 6.84-6.88 (2H, m), 7.90-7.93 (2H, m) m/z(ES+) (M+H)+=275

1-Cyclopropylpiperazine used as starting material was prepared asfollows:—

A solution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (0.792 g,3.50 mmol) in 4M HCl in 1,4-dioxane (4.37 mL, 17.50 mmol) was stirred atroom temperature for 3 h under nitrogen. The reaction mixture wasfiltered and washed with ether to afford crude 1-cyclopropylpiperazine(0.659 g) as a white solid. The crude product was purified by ionexchange chromatography, using a SCX column. The desired product waseluted from the column using 3.5M NH3/MeOH and pure fractions wereevaporated to dryness to afford 1-cyclopropylpiperazine (0.264 g, 59.7%)as a yellow oil.

1H NMR (399.9 MHz, DMSO-d6) δ 0.25-0.30 (2H, m), 0.35-0.40 (2H, m),1.54-1.60 (1H, m), 2.43 (4H, t), 2.60-2.65 (4H, t), 3.30 (1H, s)

tert-Butyl 4-cyclopropylpiperazine-1-carboxylate used as startingmaterial was prepared as follows:—

MeOH (0.3 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (2 g, 11.47mmol) and acetic acid (1.051 mL, 18.35 mmol) were added to a stirredsolution of tert-butyl piperazine-1-carboxylate (1.068 g, 5.735 mmol) inTHF (40 mL) under nitrogen. Sodium cyanoborohydride (0.541 g, 8.60 mmol)was added portionwise over a period of 10 mins. The resulting mixturewas stirred at 60° C. for 24 h. The reaction mixture was evaporated todryness and mixed with water (80 mL) and 1M HCl (25 mL). This solutionwas washed with EtOAc (2×50 mL), the aqueous layer was basified withK₂CO₃, and extracted with EtOAc (2×30 mL). The organic layers werecombined, washed with saturated brine (30 mL), dried over MgSO₄,filtered and evaporated to afford tert-butyl4-cyclopropylpiperazine-1-carboxylate (0.792 g, 61.1%) as a colourlessoil which crystallised on standing.

1H NMR (399.9 MHz, DMSO-d6) δ 0.30-0.34 (2H, m), 0.40-0.44 (2H, m), 1.41(9H, s), 1.60-1.65 (1H, m), 2.47 (4H, t), 3.26 (4H, t)

Example 894-(4-Cyclobutylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide

4-(4-cyclobutylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamidewas prepared as for Example 94, but starting from ethyl4-(4-cyclobutylpiperazin-1-yl)benzoate (202 mg, 0.7 mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (basic) using a39-59% gradient of acetonitrile in water containing 1% 0.880 ammonia.The clean fractions were combined and evaporated to afford the titlecompound (21 mg, 6%); ¹H NMR (399.9 MHz, DMSO-d₆) δ 1.61-1.71 (2H, m),1.81-1.86 (2H, m), 1.99-2.02 (2H, m), 2.38 (4H, t), 2.75 (1H, s),2.85-2.87 (4H, m), 3.26-3.27 (4H, m), 3.72 (6H, d), 6.33 (1H, t),6.42-6.43 (2H, m), 6.45 (1H, s), 6.95 (2H, d), 7.90 (2H, d), 10.29 (1H,s), 12.07 (1H, s). MS=m/z 490 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.009 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate, used as starting material,was prepared as follows:

Ethyl 4-fluorobenzoate (0.225 mL, 1.53 mmol) and 1-cyclobutylpiperazine(0.430 g, 3.07 mmol) were taken up in DMA (3 mL) and sealed into amicrowave tube. The reaction was heated to 150° C. for 90 mins in themicrowave reactor and cooled to room temperature. The reaction was notcomplete, so it was reheated at 150° C. for a further 1 h. The reactionmixture was evaporated to dryness and the crude product purified bysilica column chromatography, eluting with a gradient of 0-2.5% MeOH inDCM. Pure fractions were evaporated to dryness to afford ethyl4-(4-cyclobutylpiperazin-1-yl)benzoate (0.050 g, 11.31%) as a yellowsolid.

1H NMR (399.9 MHz, CDCl3) δ 1.29 (3H, t), 1.65-1.70 (2H, m), 1.86 (2H,t), 2.00 (2H, q), 2.41 (4H, d), 2.68-2.75 (1H, m), 3.27 (4H, t), 4.25(2H, q), 6.79 (2H, d), 7.85 (2H, d). MS=m/z=289 (MH+).

1-Cyclobutylpiperazine, used as starting material, was prepared asfollows:—

Trifluoroacetic acid (7.84 mL, 101.73 mmol) was added to a stirredsolution of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (2.445 g,10.17 mmol) in DCM (25 mL) cooled to 0° C. under nitrogen and stirred at20° C. for 24 h. The reaction mixture was evaporated to dryness anddiluted with DCM (30 mL). This was then washed with saturated NaHCO₃(2×10 mL) and the organic layers evaporated to dryness. Product wasstill present in the aqueous layer, so this was basified with 2M NaOHand extracted with DCM (3×10 mL) and EtOAc (1×10 mL). Organic fractionswere combined and evaporated to dryness to afford 1-cyclobutylpiperazine(0.430 g, 30.1%). 1H NMR (399.9 MHz, DMSO-d6) δ 1.60-1.67 (2H, m),1.72-1.80 (2H, m), 1.93-1.97 (2H, m), 2.25 (4H, s), 2.57-2.60 (1H, d),2.82 (4H, t)

tert-Butyl 4-cyclobutylpiperazine-1-carboxylate, used as startingmaterial, was prepared as follows:—

Water (0.3 mL), cyclobutanone (2.000 g, 28.53 mmol) and acetic acid(3.48 mL, 60.86 mmol) were added to a stirred solution of tert-butylpiperazine-1-carboxylate (3.54 g, 19.02 mmol) in THF (40 mL) undernitrogen. Sodium cyanoborohydride (1.793 g, 28.53 mmol) was addedportionwise over a period of 10 mins. The resulting mixture was stirredat 60° C. for 19 h. The reaction mixture was evaporated to dryness andmixed with water (80 mL) and 1M HCl (25 mL). The solution was washedwith EtOAc (2×50 mL), basified with K₂CO₃ and extracted with EtOAc (2×30mL). The organic layer was washed with saturated brine and dried overMgSO₄, filtered and evaporated to afford pure tert-butyl4-cyclobutylpiperazine-1-carboxylate (2.445 g, 53.5%) as a colourlessoil.

1H NMR (399.9 MHz, DMSO-d6) δ 1.40 (9H, s), 1.60-1.65 (2H, m), 1.75-1.80(1H, m), 1.90-2.00 (2H, m), 2.17 (1H, t), 2.65-2.75 (1H, m), 3.30 (4H,d). MS=m/z 241 (MH+).

Example 904-(4-Acetylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]benzamide

4-(4-acetylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamidewas prepared as for Example 94, but starting from methyl4-(4-acetylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (basic) using a31-51% gradient of acetonitrile in water, containing 1% 0.880 ammonia.The clean fractions were taken and evaporated to afford the titlecompound as a white solid (3 mg, 1.0%); ¹H NMR (399.9 MHz, DMSO-d₆) δ2.06 (3H, s), 2.78 (4H, s), 3.28 (2H, s) 3.25 (2H, t), 3.49-3.56 (4H,m), 3.73 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.45 (1H, s), 6.99 (2H,d), 7.92 (2H, d), 10.32 (1H, s), 12.08 (1H, s).

MS: m/z 478 (MH+).

Mean of n=5, FGFR Kinase assay—Caliper, IC₅₀ 0.056 μM.

A deoxygenated suspension of 1-acetylpiperazine (0.308 g, 2.40 mmol),methyl 4-bromobenzoate (0.430 g, 2 mmol), tri-potassium orthophosphate(0.594 g, 2.80 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.164 g, 0.40mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.092 g, 0.10 mmol)in toluene (10 mL) was stirred at 100° C., over a period of 24 h undernitrogen. The cooled reaction mixture was filtered and evaporated togive crude product. The crude product was purified by silica columnchromatography, eluting with a gradient 0-5% MeOH in DCM. Pure fractionswere evaporated to dryness to afford methyl4-(4-acetylpiperazin-1-yl)benzoate (0.295 g, 56.2%) as a yellow solid.

1H NMR (399.9 MHz, CDCl3) δ 2.07 (3H, s), 3.24-3.30 (4H, m), 3.56 (2H,t), 3.70-3.72 (2H, m), 3.80 (3H, s), 6.78-6.81 (2H, m), 7.85-7.89 (2H,m). MS: m/z 263 (MH+).

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 91N-[5-[2-(3-Methoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(4-methylsulfonylpiperazin-1-yl)benzamide

A solution of formic acid (5 mL, 130.36 mmol) andN-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide(255 mg, 0.47 mmol) was stirred at 85° C. for 2 h. The reaction mixturewas cooled and evaporated to dryness. The crude product was purified byreverse phase prep. HPLC (basic) using a 36-46% gradient of acetonitrilein water, containing 1% 0.880 ammonia. The clean fractions were combinedand evaporated to afford the title compound (43.0 mg, 18.82%) as a whitesolid; ¹H NMR (499.9 MHz, DMSO_(d)6+CD₃CO₂D) δ 2.87 (3H, s), 2.88-2.92(4H, m), 3.28-3.32 (4H, m), 3.39-3.42 (4H, m), 3.73 (3H, s), 6.30 (1H,s), 6.71-6.74 (1H, m), 6.77 (1H, s0, 6.80 (2H, d), 6.94-6.98 (2H, m),7.16 (1H, t), 7.85-7.89 (2H, m).

MS: m/z=484 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.25 μM.

N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamideused as starting material was prepared as follows:—

Methanesulphonyl chloride (0.042 mL, 0.55 mmol) was added at 0° C. to asolution ofN-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamide(0.231 g, 0.5 mmol) and N,N-diethylethanamine (0.077 mL, 0.55 mmol) inDCM (4 mL). The resulting solution was stirred at 20° C. for 1 h. Thereaction mixture was diluted with saturated sodium hydrogen carbonate(10 ml) filtered and the solid washed with DCM (2×10 ml). The organiclayers were combined and washed with water (20 ml) and saturated brine(20 ml). The organics were dried (MgSO₄), filtered and evaporated toafford crude product. The crude product was purified by silica columnchromatography, eluting with a gradient of 0-5% MeOH in DCM. Purefractions were evaporated to dryness to affordN-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide(0.255 g, 94%) as a white solid. MS: m/z=540 (MH+).

N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamidewas prepared as follows:—

A 2M solution of trimethylaluminium in toluene (6.25 mL, 12.50 mmol) wasadded dropwise to a stirred solution of and1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-amine (1.367 g, 5.00mmol) and ethyl 4-(piperazin-1-yl)benzoate (1.171 g, 5 mmol) in toluene(20 mL) at 4° C., over a period of 5 mins under nitrogen. The resultingsolution was stirred at 20° C. for 18 h. The reaction mixture wasquenched with methanol (20 mL), filtered and evaporated to afford tansolid. The crude product was purified by silica column chromatography,eluting with a gradient of 0 to 10% MeOH in DCM and 0.1% ammonia. Purefractions were evaporated to dryness to affordN-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamide(0.520 g, 22.53%) as a white solid.

1H NMR (399.9 MHz, CDCl₃) δ 1.59 (9H, s), 2.81-2.91 (4H, m), 2.96-2.99(4H, m), 3.23 (3H, t), 3.25-3.42 (1H, m), 3.72 (3H, s), 6.17 (1H, s),6.64-6.68 (1H, m), 6.73 (1H, t), 6.78 (1H, d), 6.84-6.88 (2H, m), 7.12(1H, t), 7.38 (1H, s), 7.67-7.71 (2H, m).

Piperazine (17.23 g, 200.00 mmol) was added to ethyl 4-fluorobenzoate(7.34 mL, 50 mmol), in DMSO (50 mL) warmed to 120° C. under nitrogen.The resulting solution was stirred at 120° C. for 20 h. The reactionmixture was cooled and the solvent evaporated. The product waspartitioned between saturated aq. sodium hydrogen carbonate solution(100 ml) and ethyl acetate (100 ml). This was extracted with ethylacetate (2×75 ml), washed with brine solution, dried over MgSO₄,filtered and evaporated. The crude product was purified by silica columnchromatography, eluting with 10% methanol in dichloromethane containing0.1% 0.880 ammonia. Pure fractions were evaporated to dryness to affordthe product as a solid.

The insoluble solid was slurried in DCM (500 ml) and stirred for 1 h.This solution was filtered and the organic solution dried over MgSO₄,filtered and evaporated to give the bulk of the product as a solid. Thesolids were combined to give ethyl 4-(piperazin-1-yl)benzoate (9.53 g,81%). 1H NMR (399.9 MHz, CDCl₃) δ 1.28-1.32 (3H, m), 2.94-2.96 (4H, m),3.20-3.22 (4H, m), 4.26 (2H, q), 6.77-6.81 (2H, m), 7.84-7.87 (2H, m).MS: m/z=236 (MH+)

5-[2-(3-methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine was preparedas outlined in Example 13.

Example 92N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(1-methyl-4-piperidyl)benzamide

A solution of NaHMDS (1M in THF) (5.91 mL, 5.91 mmol) was added dropwiseto a stirred solution of methyl 4-(1-methylpiperidin-4-yl)benzoate(0.4594 g, 1.97 mmol) and tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate(0.821 g, 2.36 mmol) in THF (4 mL), over a period of 10 mins undernitrogen. The resulting solution was stirred at room temperature for 18h. The reaction mixture was poured into saturated NH₄Cl (25 mL),extracted with EtOAc (2×25 mL), washed with saturated brine and driedover MgSO₄, filtered and evaporated to afford the crude product (1.0719g) as an orange gum. The crude product was purified by preparative HPLCusing decreasingly polar mixtures of water (containing 1% NH3) and MeCNas eluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (0.142 g, 16.08%) as a white solid;

¹H NMR (399.9 MHz, DMSO-d6) δ 1.64-1.78 (4H, m), 1.97-2.01 (2H, m), 2.22(3H, s), 2.53-2.58 (1H, m), 2.88-2.91 (6H, m), 3.73 (6H, s), 6.33 (1H,t), 6.42-6.44 (3H, m), 7.35 (2H, d), 7.93 (2H, d), 10.57 (1H, s), 12.08(1H, s)

MS: m/z 449 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper, IC₅₀ 0.0079 μM.

Methyl 4-(1-methylpiperidin-4-yl)benzoate, used as starting material,was prepared as follows:—

Water (0.2 mL), paraformaldehyde (0.470 g, 15.64 mmol) and acetic acid(0.895 mL, 15.64 mmol) were added to a stirred suspension of4-(4-(methoxycarbonyl)phenyl)piperidinium chloride (1 g, 3.91 mmol) inTHF (20 mL) under nitrogen. Sodium cyanoborohydride (0.369 g, 5.87 mmol)was added portionwise over a period of 10 mins. The resulting mixturewas stirred at 60° C. for 19 h. The reaction mixture was evaporated todryness and mixed with water (20 mL) and 1M HCl (5 mL). The solution waswashed with EtOAc (2×15 mL), basified with K₂CO₃ and extracted withEtOAc (2×15 mL). The organic layer was washed with saturated brine anddried over MgSO₄, filtered and evaporated to afford pure methyl4-(1-methylpiperidin-4-yl)benzoate (0.459 g, 50.4%) as a colourless oilwhich crystallised on standing.

1H NMR (399.9 MHz, DMSO-d6) δ 1.63-1.72 (2H, m), 1.73-1.77 (2H, m),1.96-2.03 (2H, m), 2.21 (3H, s), 2.87-2.90 (2H, m), 3.85 (3H, s),4.30-4.31 (1H, m), 7.40 (2H, d), 7.88-7.91 (2H, m)

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 934-(3,4,6,7,8,8a-Hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

4-(3,4,6,7,8,8a-Hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamidewas prepared as for Example 94, but starting from methyl4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (193mg, 0.7 mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (basic) using a33-53% gradient of acetonitrile in water, containing 1% 0.880 ammonia.The clean fractions were combined and evaporated to afford the titlecompound (34 mg, 10%); ¹H NMR (399.9 MHz, DMSO-d₆) δ 1.37-1.41 (1H, m),1.67-1.77 (2H, m), 1.84-1.88 (1H, m), 1.99-2.06 (1H, m), 2.09 (1H, t),2.18-2.25 (1H, m), 2.80-2.84 (1H, m), 2.87 (4H, s), 3.01-3.06 (2H, m),3.73 (6H, s), 3.80-3.83 (1H, m), 3.96-3.98 (1H, m), 6.33 (1H, t),6.42-6.45 (3H, m), 6.97 (2H, d), 7.90 (2H, d), 10.28 (1H, s), 12.07 (1H,s)

MS=m/z 476 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.037 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate,used as starting material was prepared as follows:—

Methyl 4-iodobenzoate (2.076 g, 7.92 mmol), cesium carbonate (5.16 g,15.85 mmol), 2-acetylcyclohexanone (0.209 mL, 1.58 mmol) and copper(I)iodide (0.075 g, 0.40 mmol) were added to a stirred solution1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (1 g, 7.92 mmol) in DMF(20 mL) under nitrogen. The resulting suspension was stirred at 90° C.for 20 h. The reaction mixture was evaporated to dryness and redissolvedin a mixture of methanol and water. The crude product was purified byion exchange chromatography, using a SCX column. The desired product waseluted from the column using 3.5M NH3/MeOH and pure fractions wereevaporated to dryness to afford the desired compound (1.243 g, 60.2%) asa brown gum.

1H NMR (399.9 MHz, DMSO-d6) δ 1.33-1.43 (1H, m), 1.57-1.79 (3H, m),1.81-1.89 (1H, m), 1.99-2.03 (1H, m), 2.07 (1H, q), 2.16-2.23 (1H, m),2.56 (1H, t), 2.83-2.95 (2H, m), 3.00-3.05 (2H, m), 3.06-3.09 (1H, m),3.75-3.78 (3H, m), 3.86 (1H, t), 3.98-4.01 (1H, m), 6.98-7.02 (2H, m),7.77-7.80 (2H, m).

MS=m/z 261 (MH+).

Example 944-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

A 1M solution of NaHMDS in THF (1.13 ml, 1.05 mmol) was added to astirred solution of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244mg, 0.7 mmol) and methyl4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate (231 mg,0.84 mmol) in THF (5 ml) at 0° C. under nitrogen, over 5 minutes. Thereaction mixture was stirred for an additional 5 minutes at 0° C., thenstirred at 20° C. for 18 h. An additional amount of tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (80mg, 0.23 mmol) was added with 1M NaHMDS in THF (1.13 ml, 1.13 mmol). Thereaction mixture was stirred for an additional 3 h. The reaction mixturewas quenched with saturated ammonium chloride (20 ml) and extracted withethyl acetate (3×20 ml). The extracts were washed with saturated brinesolution (15 ml), dried (MgSO₄) and evaporated to give crude product.The crude product was purified by reverse phase prep. HPLC (basic) usinga 38-58% gradient of acetonitrile in water containing 1% 0.880 ammoniumhydroxide. The clean fractions were taken and evaporated to afford thetitle compound as a white solid (32 mg, 9%); ¹H NMR (500.13 MHz,DMSO-d₆) δ 1.25 (1H, s), 1.62 (2H, t), 1.72 (1H, d), 1.93-1.95 (2H, m),2.19-2.20 (1H, m), 2.44 (1H, s), 2.81 (3H, q), 2.87 (4H, s), 3.28 (1H,s), 3.69 (1H, s), 3.72 (6H, s), 3.77 (1H, d), 6.33 (1H, t), 6.42 (2H,d), 6.44 (1H, s), 6.96 (2H, d), 7.89 (2H, d), 10.29 (1H, s), 12.07 (1H,s). MS: m/z 490 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.081 μM.

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Methyl 4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate,used as starting material, was prepared as follows:—

A solution of 2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (5 g)in a mixture of methanol and water (1:1) was converted to the freebaseby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and pure fractions wereevaporated to dryness to afford the desired compound (1.5224 g, 10.86mmol) as a yellow solid.

Methyl 4-iodobenzoate (2.84 g, 10.86 mmol), cesium carbonate (7.07 g,21.71 mmol), 2-acetylcyclohexanone (0.286 mL, 2.17 mmol) and copper(I)iodide (0.103 g, 0.54 mmol) were added to a stirred solution of2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (1.5224 g, 10.86mmol) in DMF (30 mL) under nitrogen. The resulting suspension wasstirred at 90° C. for 20 h. The reaction mixture was evaporated todryness and dissolved in methanol. The crude product was purified by ionexchange chromatography, using a SCX column. The desired product waseluted from the column using 3.5M NH3/MeOH and pure fractions wereevaporated to dryness to afford a brown gum. This was purified again bysilica column chromatography, eluting with 5% MeOH (containing 0.1%ammonium hydroxide) in DCM. Pure fractions were evaporated to dryness toafford the desired compound (0.503 g, 16.8%) as an orange solid ¹H NMR(399.9 MHz, CDCl₃) δ 1.29-1.33 (1H, m), 1.26-1.40 (1H, m), 1.62 (1H, d),1.64 (1H, d), 1.65-1.68 (1H, m), 1.69 (1H, s), 1.80-1.82 (1H, m),2.04-2.10 (2H, m), 2.32-2.39 (1H, m), 2.61 (1H, d), 2.89 (2H, d),3.01-3.08 (1H, m), 3.58-3.63 (1H, m), 3.70-3.75 (1H, m), 3.86 (3H, s),6.83-6.87 (2H, m), 7.89-7.93 (2H, m). MS m/z=275 (MH+).

Example 95N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide

A solution of NaHMDS (1M in THF) (2.83 mL, 2.83 mmol) was added dropwiseto a stirred solution of methyl4-((4-methylpiperazin-1-yl)methyl)benzoate (0.351 g, 1.41 mmol) andtert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate(0.589 g, 1.70 mmol) in THF (3 mL), over a period of 10 mins undernitrogen. DMA (3 mL) was added. The resulting solution was stirred atroom temperature for 60 h. A further aliquot of NaHMDS (1.415 mL, 1.415mmol) was added dropwise and the solution was stirred at roomtemperature for a further 90 mins. The reaction mixture was poured intosaturated NH₄Cl (25 mL), extracted with EtOAc (2×25 mL), washed withsaturated brine and dried over MgSO₄, filtered and evaporated to affordthe crude product (0.8776 g) as an orange gum. The crude product waspurified by preparative HPLC using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(0.034 g, 5.19%) as a white solid; ¹H NMR (500.0 MHz, DMSO-d6) δ 2.18(3H, s), 2.34-2.37 (2H, m), 3.54 (2H, s), 3.73 (3H, s), 6.32-6.33 (1H,t), 6.41-6.42 (2H, d), 7.38-7.39 (1H, d), 7.90-7.92 (1H, d), 10.02 (1H,s), 11.79 (1H, s)

MS: m/z 464 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper, IC₅₀ 0.14 μM.

Methyl 4-((4-methylpiperazin-1-yl)methyl)benzoate, used as startingmaterial was prepared as follows:

A solution of (trimethylsilyl)diazomethane ((0.611 mL, 3.84 mmol) 2.0Min diethyl ether) was added dropwise to a stirred suspension of4-((4-methylpiperazin-1-yl)methyl)benzoic acid (0.75 g, 3.20 mmol) intoluene (21 mL) and methanol (7 mL) over a period of 10 mins undernitrogen. The resulting suspension was stirred at room temperature for 3h. A further aliquot of (trimethylsilyl)diazomethane (1.222 mL, 7.68mmol) was added dropwise and the solution was stirred at roomtemperature for a further 18 h. The reaction mixture was evaporated todryness to afford the crude product (0.723 g) as a white solid. This wastaken up in DCM and the insolubles were filtered off. The filtrate wasevaporated to dryness to afford the crude product. This was taken up inDCM again and more insolubles were filtered off to afford methyl4-((4-methylpiperazin-1-yl)methyl)benzoate (0.351 g, 44.2%), which wasused without purification.

1H NMR (399.9 MHz, CDCl3) δ 2.60-2.61 (3H, m), 2.77 (4H, t), 2.99 (4H,s), 3.58 (1H, s), 3.62 (1H, s), 3.85 (2H, d), 7.29-7.38 (2H, m),7.92-7.80 (2H, m)

MS: m/z 249 (MH+)

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 96N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4,5-trimethylpiperazin-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4,5-trimethylpiperazin-1-yl)benzamidewas prepared following the procedure as for Example 94, but startingfrom ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate (310 mg, 0.86mmol), tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (225mg, 0.65 mmol) and 1M NaHMDS (2.59 ml, 2.59 mmol) in THF (5 ml). Thecrude product was purified by reverse phase prep. HPLC (basic) using a38-58% gradient of acetonitrile in water containing 1% 0.880 ammonia.The clean fractions were taken and evaporated to afford the titlecompound as a white solid (23 mg, 5.6%); ¹H NMR (399.99 MHz, CDCl₃)δ1.09 (6H, d), 2.17-2.28 (2H, m), 2.22 (3H, s), 2.56 (2H, t), 2.81-2.90(4H, m), 3.48 (2H, d), 3.68 (6H, s), 6.22 (1H, t), 6.28 (2H, s), 6.56(1H, s), 6.78 (2H, d), 7.68 (2H, d0, 8.86 (1H, s), 9.65 (1H, s). MS: m/z464 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00054 μM.

Ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate used as startingmaterial was prepared as follows:—

Titanium(IV) isopropoxide (0.598 mL, 2.00 mmol) was added to ethyl4-(3,5-dimethylpiperazin-1-yl)benzoate (0.262 g, 1 mmol), andparaformaldehyde (0.120 g, 4.00 mmol) in ethanol (5 mL). The resultingsolution was stirred at 60° C. under nitrogen for 30 mins. This wascooled to 20° C. and sodium borohydride (0.095 g, 2.5 mmol) was added inone portion. The solution was heated at 60° C. for 24 h. The reactionmixture was quenched with 0.880 ammonia (0.5 mL), filtered, washed withdiethyl ether (2×5 mL) and the organic extracts were evaporated. Thecrude product was purified by silica column chromatography, eluting witha gradient of 0-5% MeOH in DCM containing 0.1% ammonia. Fractions wereevaporated to dryness to afford an oil. This was dissolved inacetonitrile (20 ml), polymer supported isocyante resin (1 mmol/g, 2 g)was added and the suspension was stirred overnight. The resin wasfiltered off and the solution evaporated to dryness to give ethyl4-(3,4,5-trimethylpiperazin-1-yl)benzoate (0.310 g, 112%) as a whitesolid. MS: m/z 278 (MH+).

tert-butyl5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate, usedas starting material was prepared as in Example 2.

Example 97N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxamide

2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was addeddropwise to a stirred solution of ethyl5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.268 g, 1 mmol)and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride(0.286 g, 1.00 mmol) in toluene (7.14 ml) at 80° C. under nitrogen for 4h and then at 70° C. for 18 h.

Ethyl acetate (5 mL) was added to the reaction mixture followed by asolution of potassium sodium tartrate (5 mL, 20% aqueous). More ethylacetate (50 mL) and water (25 mL) was added and the mixture was filteredthrough celite. The filtrate was transferred to a separating funnel andthe aqueous layer removed. The ethyl acetate layer was washed withsaturated brine and then dried over magnesium sulphate. After filtrationthe solvent was evaporated to give the crude product as a yellow gum.The crude product was purified by preparative LCMS, using decreasinglypolar mixtures of water (containing 1% NH3) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford the title compound (0.036 g, 7.63%) as a white solid.

1H NMR (500.13 MHz, DMSO-d6) δ 1.07 (3H, d), 2.26-3.12 (4H, m),3.38-3.47 (3H, m), 3.78 (6H, s), 5.09 (2H, s), 5.55 (1H, s), 6.17 (1H,d), 6.45 (1H, s), 6.61 (2H, d), 7.64 (1H, s).

MS: m/z 472 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00046 μM.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as in Example 12.

Ethyl 5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxylate, used asstarting material was prepared as follows:

Palladium(II) acetate (0.112 g, 0.50 mmol) was added to a mixture ofethyl 5-bromothiophene-2-carboxylate (0.571 g, 5 mmol),1,2-dimethyl-piperazine (1.175 g, 5 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) andcesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C.under nitrogen. The resulting suspension was stirred at 110° C. for 23h. The crude product was purified by ion exchange chromatography, usinga SCX2 column. The crude material was dissolved in methanol and thenapplied to the column. The desired product was eluted from the columnusing 2M NH3 in methanol and pure fractions were evaporated to drynessto afford the crude product as a brown oil. This material was furtherpurified by silica column chromatography, eluting with a gradient of 1to 5% MeOH in DCM. Pure fractions were evaporated to dryness to affordethyl 5-(3,4-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.640 g,47.7%) as a light brown solid.

1H NMR (399.9 MHz, CDCl3) δ 1.11-1.13 (3H, m), 1.33 (3H, t), 2.24-2.29(1H, m), 2.33 (3H, s), 2.37-2.44 (1H, m), 2.73 (1H, d), 2.82-2.87 (1H,m), 3.08-3.14 (1H, m), 3.36-3.40 (1H, m), 3.43-3.48 (1H, m), 4.28 (2H,q), 6.01 (1H, d), 7.54 (1H, d)

MS: m/z 269 (MH+)

Example 984-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide

A 2M solution of trimethylaluminium in toluene (0.853 mL, 1.71 mmol) wasadded dropwise to a stirred solution of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.170 g, 0.68 mmol)and methyl4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate (0.187g, 0.68 mmol) in toluene (10 mL), over a period of 5 mins undernitrogen. The resulting solution was stirred at room temperature for 18h. The reaction was incomplete, so further trimethylaluminium (0.853 mL,1.71 mmol) was added dropwise over a period of 5 mins and the solutionwas stirred at 60° C. for 4 h. The reaction mixture was cooled andpoured into acetone (50 mL), quenched with damp sodium sulphite,filtered and evaporated to dryness. The crude product was purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to the title compound (0.105 g, 31.3%) as awhite solid.

1H NMR (500.13 MHz, DMSO-d6) δ 1.21-1.26 (1H, m), 1.30-1.33 (1H, m),1.53-1.57 (1H, m), 1.63 (1H, d), 1.65 (1H, d), 1.76 (1H, d), 1.98 (1H,d), 1.98-2.03 (1H, m), 2.22-2.27 (1H, m), 2.55 (1H, d), 2.79 (1H, t),2.83 (2H, d), 3.68-3.70 (1H, m), 3.78 (7H, s), 5.10 (2H, s), 5.67 (1H,s), 6.46 (1H, t), 6.61-6.62 (2H, m), 6.97 (2H, d), 7.84 (2H, d), 10.20(1H, s), 11.15 (1H, s). MS: m/z 492 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.003 μM.

Methyl 4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoateused as starting material was prepared as follows:

A solution of 2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazinedihydrochloride (5 g) in methanol (20 ml) and water (10 ml) was purifiedby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and pure fractions wereevaporated to dryness to afford2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (1.5224 g, 10.86mmol) as a yellow solid.

Methyl-4-iodobenzoate (2.84 g, 10.86 mmol), cesium carbonate (7.07 g,21.71 mmol), 2-acetylcyclohexanone (0.286 mL, 2.17 mmol) and copper(I)iodide (0.103 g, 0.54 mmol) were added to a stirred solution of2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (1.5224 g, 10.86mmol) in DMF (30 mL) under nitrogen. The resulting suspension wasstirred at 90° C. for 20 h. The reaction mixture was evaporated todryness. The crude product was purified by ion exchange chromatography,using a SCX column. The desired product was eluted from the column using3.5M NH3/MeOH and fractions were evaporated to dryness to afford thecrude product as an impure brown gum. The crude product was purified bysilica column chromatography, eluting with 5% MeOH, 0.1% aqueous ammoniain DCM. Pure fractions were evaporated to dryness to afford the desiredcompound (0.681 g, 22.87%) as an orange solid.

1H NMR (399.9 MHz, CDCl3) δ 1.29-1.33 (1H, m), 1.26-1.40 (1H, m), 1.62(1H, d), 1.64 (1H, d), 1.65-1.68 (1H, m), 1.69 (1H, s), 1.80-1.82 (1H,m), 2.04-2.10 (2H, m), 2.32-2.39 (1H, m), 2.61 (1H, d), 2.89 (2H, d),3.01-3.08 (1H, m), 3.58-3.63 (1H, m), 3.70-3.75 (1H, m), 3.86 (3H, s),6.83-6.87 (2H, m), 7.89-7.93 (2H, m). MS: m/z 275 (MH+).

Example 994-(1-Cyclopropylpiperidin-4-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

Methyl 4-(1-cyclopropylpiperidin-4-yl)benzoate (0.259 g, 1 mmol),5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol)in toluene (10 ml) was treated with a 2M solution of trimethylaluminium(1.250 ml, 2.50 mmol) in toluene, under nitrogen. The reaction mixturewas heated at 60° C. for 18 h. The reaction mixture was cooled and thereaction quenched with methanol (40 ml) and acidified with 2N HCl (1ml). The crude reaction mixture was purified by ion exchangechromatography, using an SCX column. The crude product was eluted fromthe column using 7M NH3/MeOH and fractions were evaporated to dryness.The crude product was purified by silica column chromatography, elutingwith a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractionswere evaporated to dryness and the product crystallised from DCM/diethylether to give the title compound (0.170 g, 35.8%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.31-0.33 (2H, m), 0.43-0.45 (2H, m),1.58-1.66 (3H, m), 1.74 (1H, d), 1.77 (1H, s), 2.25-2.30 (2H, m), 2.55(1H, d), 2.88 (4H, s), 3.05 (2H, d), 3.73 (6H, s), 6.33 (1H, t), 6.42(2H, d), 6.47 (1H, s), 7.34 (2H, d), 7.92 (2H, d), 10.54 (1H, s), 12.13(1H, s). MS: m/z 475 (MH+).

Mean of n=3, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00091 μM.

Methyl 4-(1-cyclopropylpiperidin-4-yl)benzoate used as starting materialwas prepared as follows:

Methyl 4-piperidin-4-ylbenzoate (1.279 g, 5 mmol) was dissolved in amixture of THF (15 mL) and methanol (1 mL).[(1-Ethoxycyclopropyl)oxy]trimethylsilane (2.001 mL, 10.00 mmol) addedfollowed by acetic acid (0.916 mL, 16.00 mmol). DCM (15.00 mL) was addedto aid solubility. Solid sodium cyanoborohydride (0.471 g, 7.50 mmol)was added in portions over 5 mins. The reaction was stirred at 60° C.for 18 h. This was cooled, quenched with saturated ammonium chloridesolution (5 ml), diluted with methanol (20 ml) and partly purified byion exchange chromatography, using an SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and pure fractions wereevaporated to dryness to afford an oil. The crude product was purifiedby silica column chromatography, eluting with 5% MeOH in DCM. Purefractions were evaporated to dryness to afford the desired compound(0.548 g, 42.3%) as a white solid.

1H NMR (399.9 MHz, CDCl3) δ 0.42-0.50 (4H, m), 1.60-1.65 (2H, m),1.70-1.75 (1H, m), 1.80-1.85 (2H, m), 2.25-2.32 (2H, m), 2.55-2.61 (1H,m), 3.15-3.18 (2H, m), 3.89 (3H, s), 7.27-7.30 (2H, m), 7.94-7.97 (2H,m). MS: m/z 260 (MH+).

Methyl 4-piperidin-4-ylbenzoate was prepared as follows:—

Methyl 4-(piperidin-4-yl)benzoate hydrochloride (5.0 g, 17 mmol) wasconverted to the freebase by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand pure fractions were evaporated to dryness to afford methyl4-(piperidin-4-yl)benzoate (4.20 g, 95%) as a white solid. MS: m/z 260(MH+).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 100N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide

A 2M solution of trimethylaluminium in toluene (1.875 mL, 3.75 mmol) wasadded dropwise to a stirred suspension of ethyl4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.394 g, 1.50 mmol) and5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.374 g, 1.5 mmol)in toluene (10 mL) at 20° C., over a period of 5 mins under nitrogen.The resulting solution was stirred at 60° C. for 5 h. The reactionmixture was cooled and the reaction quenched by diluting with acetone(100 ml) and excess damp sodium sulphite added in portions. This wasstirred for 60 mins. The resulting solid filtered off, washed with 10%methanol in DCM. The filtrate was evaporated to give crude product. Thecrude product was purified by silica column chromatography, eluting witha gradient of 0 to 5% 2M ammonia/MeOH in DCM. Pure fractions wereevaporated to dryness to afford the title compound (0.287 g, 41.1%) as awhite solid. 1H NMR (500.13 MHz, DMSO-d6) δ 1.08 (6H, d), 2.31 (2H, t),3.70-3.73 (2H, m), 3.78 (6H, s), 5.10 (2H, s), 5.64 (1H, s), 6.46 (1H,t), 6.62 (2H, d), 6.95-6.97 (2H, m), 7.83-7.85 (2H, m), 10.21 (1H, s),11.09 (1H, s). MS: m/z 466 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0014 μM.

Ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate used as startingmaterial was prepared as follows.

(2S,6R)-2,6-dimethylpiperazine (6.85 g, 60.00 mmol) was added to ethyl4-fluorobenzoate (2.201 mL, 15 mmol), in DMSO (40 mL) warmed to 120° C.under nitrogen. The resulting solution was stirred at 120° C. for 20 h.The reaction mixture was cooled and the solvent evaporated. The crudeproduct was purified by silica column chromatography, eluting with agradient of 0 to 10% methanol in dichloromethane containing 1% 880ammonia. Pure fractions were evaporated to dryness to afford the desiredcompound (2.83 g, 71.9%) as a brown oil. 1H NMR (399.9 MHz, CDCl3) δ1.15 (6H, d), 1.37 (3H, t), 2.38 (1H, d), 2.41 (1H, d), 2.96-3.04 (2H,m), 3.65-3.69 (2H, m), 4.33 (2H, q), 6.84-6.87 (2H, m), 7.89-7.93 (2H,m). MS: m/z 263 (MH+).

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine was prepared asfollows: MP carbonate (2.74 mmol/g) (12.00 g, 32.88 mmol) was added to5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride (5 g,17.50 mmol) in methanol (200 mL) and water (20 mL). The resultingsuspension was stirred at room temperature for 18 h. The reactionmixture was filtered and MP carbonate was washed with 10% MeOH in DCM.This was evaporated to dryness to afford5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (2.94 g, 67.5%) asan orange waxy solid.

1H NMR (399.9 MHz, DMSO-d6) δ 3.74 (6H, s), 4.76 (1H, s), 4.97 (2H, s),6.42 (1H, t), 6.55 (2H, d).

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as in Example 12.

Example 101N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide

N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamidewas prepared following the procedure for Example 100, but staring fromethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.394 g, 1.50 mmol),5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.374 g, 1.5 mmol)and 2M trimethylaluminium in toluene (1.875 mL, 3.75 mmol). The crudeproduct was purified by silica column chromatography, eluting with agradient of 0 to 5% 2M ammonia/MeOH in DCM. Pure fractions wereevaporated to dryness to afford the title compound (0.301 g, 43.1%) as awhite solid.

1H NMR (500.13 MHz, DMSO-d6) δ 1.06-1.10 (3H, m), 2.22-2.30 (1H, m),2.20-2.63 (4H, m), 2.61-2.65 (1H, m), 2.83-2.86 (1H, m), 2.96-3.02 (1H,m), 3.63-3.70 (2H, m), 3.78 (6H, s), 5.11 (2H, s), 5.66 (1H, s), 6.46(1H, t), 6.62 (2H, d), 6.96-6.98 (2H, m), 7.83-7.86 (2H, m), 10.15 (1H,s), 11.07 (1H, s). MS: m/z 466 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.021 μM.

Ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate used as starting materialwas prepared as follows:—

1,2-Dimethylpiperazine (2.284 g, 20.00 mmol) and ethyl 4-fluorobenzoate(1.467 mL, 10 mmol) were dissolved in DMA (12 mL) and sealed in amicrowave tube. The reaction was heated to 150° C. for 90 mins in themicrowave reactor and cooled to room temperature. The reaction mixturewas heated for a further 30 mins at 150° C. and cooled to roomtemperature. The reaction mixture was evaporated and the crude productwas purified by silica column chromatography, eluting with 5% MeOH inDCM with 0.1% 0.880 ammonia. Pure fractions were evaporated to drynessto afford ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.853 g, 32.5%)as a colourless waxy solid.

1H NMR (399.9 MHz, CDCl3) δ 1.14 (3H, d), 1.37 (3H, t), 2.20-2.25 (1H,m), 2.33 (3H, s), 2.34-2.41 (1H, m), 2.62 (1H, t), 2.87-2.91 (1H, m),2.99-3.05 (1H, m), 3.57-3.62 (1H, m), 3.65-3.70 (1H, m), 4.33 (2H, q),6.83-6.87 (2H, m), 7.90-7.94 (2H, m). MS: m/z 263.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, used as startingmaterial was prepared as in Example 100.

Example 102 tert-Butyl4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate

2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was addeddropwise to a stirred solution of tert-butyl4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylate (0.326 g, 1mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g,1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reactionmixture was stirred at 20° C. for 20 h. The temperature was increased to60° C. and the reaction mixture was stirred for 20 h and then allowed tocool. The reaction mixture was diluted with acetone (10 ml) and quenchedwith damp solid sodium sulphite. The mixture was stirred for 30 mins,and then a solution of 10% methanol in DCM (10 mL) was added and themixture stirred for a further 30 mins. The suspension was filtered andthe solid washed with 10% methanol in DCM (20 mL); the combinedfiltrates were evaporated to give a yellow foam. The crude product waspurified by silica column chromatography, eluting with a gradient of 1to 10% 2M ammonia/methanol in DCM. Pure fractions were evaporated todryness to afford the crude product. This was further purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford tert-butyl4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate(0.272 g, 50.2%) as a white dry film.

1H NMR (500.13 MHz, DMSO-d6) δ 1.46 (9H, s), 2.89-2.90 (6H, m), 3.22(4H, t), 3.52 (4H, t), 3.75 (6H, s), 6.18 (1H, d), 6.27 (1H, s), 6.34(1H, t), 6.42-6.42 (2H, m), 7.72 (1H, d), 9.81 (1H, s), 11.71 (1H, s);MS: m/z 542 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.028 μM.

tert-Butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylate,used as starting material was prepared as follows:—

2.0M (Trimethylsilyl)diazomethane solution in ether (0.525 ml, 1.05mmol) was added dropwise to a stirred solution of5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylicacid (0.312 g, 1 mmol) in methanol (2.000 ml) and the mixture wasstirred at ambient temperature for 20 h. More 2.0M(Trimethylsilyl)diazomethane solution in ether (0.500 ml, 1.00 mmol) wasadded and the mixture stirred for 2 h. The mixture was evaporated andthe crude product was purified by silica column chromatography, elutingwith a gradient of 1 to 3% EtOAc in DCM. Pure fractions were evaporatedto dryness to afford the desired compound (0.141 g, 43.2%) as a creamsolid.

1H NMR (399.9 MHz, CDCl3) δ 1.48 (9H, s), 3.22 (4H, t), 3.58 (4H, t),3.82 (3H, s), 6.06 (1H, d), 7.55 (1H, d). MS: m/z 327 (MH+)

5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylicacid, used as starting material can be prepared by the method describedin the literature (Stokes, Elaine Sophie Elizabeth; Waring, MichaelJames; Gibson, Keith Hopkinson. Preparation of amides as inhibitors ofhistone deacetylase. WO2003/092686).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 103N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(1-methylpiperidin-4-yl)benzamide

N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(1-methylpiperidin-4-yl)benzamidewas prepared following the procedure as for Example 159, but startingfrom methyl 4-(1-methylpiperidin-4-yl)benzoate (0.25 g, 1.07 mmol),5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.267 g, 1.07 mmol)and 2M trimethylaluminium in toluene (2.14 ml, 4.29 mmol). The crudeproduct was purified by silica column chromatography, eluting with agradient of 0 to 8% 2.5M NH3/MeOH in DCM. Pure fractions were evaporatedto dryness, redissolved in DCM, triturated with ether and evaporated todryness to afford the title compound (0.225 g, 46.5%) as a white solid.1H NMR (399.9 MHz, DMSO-d6) δ 1.69 (1H, d), 1.73 (2H, d), 1.77 (1H, s),1.95-2.02 (2H, m), 2.21 (3H, s), 2.88 (2H, d), 3.76 (6H, s), 5.09 (2H,s), 5.62 (1H, s), 6.45 (1H, s), 6.60 (2H, s), 7.41-7.42 (2H, m),7.89-7.91 (2H, m), 10.85 (1H, s), 11.58 (1H, s). MS: m/z 451 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00094 μM.

Methyl-4-(1-methylpiperidin-4-yl)benzoate used as starting material wasprepared as follows: Water (0.4 mL), paraformaldehyde (0.742 g, 24.71mmol) and acetic acid (1.415 mL, 24.71 mmol) were added to a stirredsuspension of methyl 4-piperidin-1-ium-4-ylbenzoate chloride (1.58 g,6.18 mmol) in THF (40 mL) under nitrogen. Sodium cyanoborohydride (0.582g, 9.27 mmol) was added portion wise over a period of 10 mins. Theresulting mixture was stirred at 60° C. for 18 h. The reaction mixturewas evaporated to dryness and mixed with water (30 mL) and 1M HCl (10mL). The solution was washed with ethyl acetate (2×25 mL), basified withsolid potassium carbonate and extracted ethyl acetate (2×25 mL). Theorganic layer was washed with saturated brine and dried over MgSO₄,filtered and evaporated to afford pure methyl4-(1-methylpiperidin-4-yl)benzoate (0.784 g, 54.4%) as a colourless oilwhich solidified on standing.

1H NMR (399.9 MHz, DMSO-d6) δ 1.62-1.71 (2H, m), 1.72-1.74 (2H, m),1.95-2.02 (2H, m), 2.21 (3H, s), 2.54-2.59 (1H, m), 2.88 (2H, d), 3.85(3H, s), 7.39-7.42 (2H, m), 7.88-7.91 (2H, m). MS: m/z 234 (MH+).

Example 1044-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide

4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamidewas prepared following the procedure as for Example 159, but startingfrom methyl4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (0.25g, 0.96 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine(0.239 g, 0.96 mmol) and 2M trimethylaluminium in toluene (1.2 ml, 2.4mmol). The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (0.124 g, 27%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.37-1.44 (1H, m), 1.67-1.74 (2H, m),1.83-1.89 (1H, m), 1.99-2.04 (1H, m), 2.08 (1H, q), 2.18-2.25 (1H, m),2.82-2.89 (1H, m), 3.01-3.06 (2H, m), 3.75 (6H, s), 3.85 (1H, d),3.99-4.02 (1H, m), 5.08 (2H, s), 5.57 (1H, s), 6.44 (1H, s), 6.59-6.60(2H, m), 7.04 (2H, d), 7.85 (2H, d), 10.61 (1H, s), 11.49 (1H, s). MS:m/z 478 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0013 μM.

Methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate,used as starting material was prepared as follows:

Methyl 4-iodobenzoate (2.076 g, 7.92 mmol), cesium carbonate (5.16 g,15.85 mmol), 2-acetylcyclohexanone (0.209 mL, 1.58 mmol) and copper(I)iodide (0.075 g, 0.40 mmol) were added to a stirred solution of1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (1 g, 7.92 mmol) in DMF(20 mL) under nitrogen. The resulting suspension was stirred at 90° C.for 20 h. The reaction mixture was evaporated to dryness and redissolvedin a mixture of methanol and water. The crude product was purified byion exchange chromatography, using a SCX column. The desired product waseluted from the column using 3.5M NH3/MeOH and pure fractions wereevaporated to dryness to afford methyl4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (1.243g, 60.2%) as a brown gum.

1H NMR (399.9 MHz, DMSO-d6) δ 1.33-1.43 (1H, m), 1.57-1.79 (3H, m),1.81-1.89 (1H, m), 1.99-2.03 (1H, m), 2.07 (1H, q), 2.16-2.23 (1H, m),2.56 (1H, t), 2.83-2.95 (2H, m), 3.00-3.05 (2H, m), 3.06-3.09 (1H, m),3.75-3.78 (3H, m), 3.86 (1H, t), 3.98-4.01 (1H, m), 6.98-7.02 (2H, m),7.77-7.80 (2H, m). MS: m/z 261 (MH+).

Example 1055-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

2,3,4,6,7,8,9,9a-Octahydro-1H-pyrido[1,2-a]pyrazine (477 mg, 3.40 mmol)was added in one portion to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(659 mg, 1.70 mmol) in anhydrous dimethylsulfoxide (1.70 ml) at 25° C.The resulting solution was stirred at 100° C. for 18 h. The crudeproduct was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHto afford impure material. The concentrated eluant was purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% formic acid) and MeCN as eluents. The sample was then put through abasic HPLC system to obtain the free base. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(395 mg, 47%) as a cream solid.

1H NMR (500.133 MHz, DMSO) δ 1.19-1.35 (3H, m), 1.51-1.60 (1H, m), 1.64(1H, t), 1.73-1.79 (1H, m), 1.93-2.08 (2H, m), 2.17-2.25 (1H, m), 2.73(1H, dd), 2.81-2.93 (6H, m), 3.13 (1H, td), 3.73 (6H, s), 4.28-4.33 (1H,m), 4.37-4.42 (1H, m), 6.32 (1H, t), 6.38-6.41 (3H, m), 8.26 (1H, d),8.70 (1H, d), 9.59 (1H, br s), 11.82 (1H, br s). MS: m/z 492 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.13 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamideused as starting material was prepared as follows:—

Trimethylaluminium (2M in toluene, 9.64 ml, 19.28 mmol) was addeddropwise to a stirred suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (1.91 g, 7.71 mmol)and methyl 5-chloropyrazine-2-carboxylate (1.33 g, 7.71 mmol) inanhydrous toluene (38.6 ml) at ambient temperature. The resultingsolution was then stirred under nitrogen at ambient temperature for 18h. The reaction was incomplete so the temperature was increased to 60°C. and the reaction mixture was stirred for a further 3 h. The reactionmixture was quenched with methanol (10 mL) and HCl (2M aqueoussolution). The mixture was diluted with EtOAc (100 mL) and water (250mL) and then acidified with HCl (2N aqueous solution). The organic layerwas removed and the aqueous further extracted with EtOAc (2×100 mL). Thecombined organics were washed with water (200 mL), brine (200 mL) driedover MgSO₄ and concentrated under reduced pressure. Upon concentration aprecipitate formed. The precipitate was collected by filtration, washedwith MeOH (10 mL) and air dried to afford the desired compound (1.88 g,63%) as a yellow solid, which was used without further purification.

1H NMR (399.9 MHz, DMSO-d₆) δ 2.88-2.89 (4H, m), 3.73 (6H, s), 6.33 (1H,t), 6.43 (2H, d), 6.49 (1H, s), 8.93 (1H, s), 9.09 (1H, s), 10.44 (1H,s), 12.31 (1H, s). MS: m/z 388 (MH+).

Example 106N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)thiophene-2-carboxamide

2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was addeddropwise to a stirred solution of ethyl5-(4-methylpiperazin-1-yl)thiophene-2-carboxylate (0.254 g, 1 mmol) and5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol)in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture wasstirred at ambient temperature for 16 h and then heated at 65° C. for 24h. Ethyl acetate (5 mL) was added to the reaction mixture followed by asolution of potassium sodium tartrate (5 mL, 20% aqueous). More ethylacetate (50 mL) and water (25 mL) was added and the mixture was filteredthrough celite. The filtrate was transferred to a separating funnel andthe aqueous layer removed. The ethyl acetate layer was washed withsaturated brine and then dried over magnesium sulphate. After filtrationthe solvent was evaporated to give the crude product as a yellow solid.The crude product was purified by preparative HPLC, using decreasinglypolar mixtures of water (containing 1% NH3) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford the title compound (0.154 g, 33.8%) as a white solid.

¹H NMR (500.13 MHz, DMSO-d6, CD3CO2D) δ 2.32 (3H, d), 2.58 (4H, t), 2.88(4H, s), 3.26 (4H, t), 3.73 (3H, s), 3.74 (3H, s), 6.13 (1H, d), 6.25(1H, s), 6.32 (1H, d), 6.40 (2H, d), 7.68-7.69 (1H, m); MS: m/z 456(MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.001 μM.

Ethyl 5-(4-methylpiperazin-1-yl)thiophene-2-carboxylate, used asstarting material was prepared as follows:

Palladium(II) acetate (0.225 g, 1.00 mmol) was added to ethyl5-bromothiophene-2-carboxylate (2.351 g, 10 mmol), 1-methylpiperazine(1.331 ml, 12.00 mmol), rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl(0.623 g, 1.00 mmol) and cesium carbonate (4.56 g, 14.00 mmol) intoluene (100 ml) at 20° C. under nitrogen. The resulting suspension wasstirred at 110° C. for 23 h. The mixture was filtered through celite andthe filtrate was evaporated to dryness to give a brown oil. The crudeproduct was purified by ion exchange chromatography, using a SCX column.The desired product was eluted from the column using 7M NH3/MeOH andpure fractions were evaporated to dryness to afford the crude product asa brown gum. This material was further purified by silica columnchromatography, eluting with a gradient of 0 to 3% methanol in DCM. Purefractions were evaporated to dryness to afford the desired compound(1.380 g, 54.3%) as an orange oil.

1H NMR (399.9 MHz, CDCl3) δ 1.33 (3H, t), 2.34 (3H, s), 2.54 (4H, t),3.28 (4H, t), 4.28 (2H, q), 6.02 (1H, d), 7.55 (1H, d); MS: m/z 255(MH+)

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 107N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)thiophene-2-carboxamide

2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was addeddropwise to a stirred solution of ethyl5-(4-methylpiperazin-1-yl)thiophene-2-carboxylate (0.254 g, 1 mmol) and5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride (0.286g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. Thereaction mixture was stirred at room temperature for 18 h and thenheated at 65° C. for 6 h. Ethyl acetate (5 mL) was added to the reactionmixture followed by a solution of potassium sodium tartrate (5 mL, 20%aqueous). More ethyl acetate (50 mL) and water (25 mL) was added and themixture was filtered through celite. The filtrate was transferred to aseparating funnel and the aqueous layer removed. The ethyl acetate layerwas washed with saturated brine and then dried over magnesium sulphate.After filtration the solvent was evaporated to give the crude product asa yellow solid. The crude product was purified by preparative HPLC,using decreasingly polar mixtures of water (containing 1% NH3) and MeCNas eluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (0.147 g, 32.1%) as a white solid.

1H NMR (500.13 MHz, DMSO-d6, CD3CO2D) δ 2.29 (3H, s), 2.53-2.55 (4H, m),3.25-3.28 (4H, m), 3.77 (6H, s), 5.09 (2H, s), 5.63 (1H, s), 6.16 (1H,d), 6.45 (1H, t), 6.60 (2H, d), 7.64 (1H, d); MS: m/z 458 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0011 μM.

Ethyl 5-(4-methylpiperazin-1-yl)thiophene-2-carboxylate, used asstarting material was prepared as outlines in Example 106.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as in Example 12.

Example 108N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3,3-dimethylpiperazin-1-yl)pyrazine-2-carboxamide

2,2-Dimethylpiperazine (343 mg, 3.00 mmol) was added in one portion to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(388 mg, 1 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. Theresulting solution was stirred at 100° C. for 18 h. The crude productwas purified by ion exchange chromatography, using a SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH to affordimpure material. The concentrated eluent was purified by preparativeHPLC, using decreasingly polar mixtures of water (containing 1% NH3) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the title compound (217 mg, 47%) as ayellow solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.06 (6H, s), 2.04 (1H, s), 2.82-2.88 (6H,m), 3.51 (2H, s), 3.65 (2H, t), 3.72 (6H, s), 6.33 (1H, t), 6.42 (2H,d), 6.46 (1H, s), 8.32 (1H, s), 8.66 (1H, s), 9.71 (1H, s), 12.17 (1H,s). MS: m/z 466 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.002 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 1095-(4-Cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(390 mg, 1.00 mmol) was added in one portion to 1-cyclopropylpiperazine,2HCl (398 mg, 2.00 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.52ml, 3.00 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. Theresulting solution was stirred at 100° C. for 18 h. The crude productwas purified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH₃/MeOH to affordimpure material. The concentrated eluent was purified by silica columnchromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM.Fractions containing desired product were evaporated to dryness to givea yellow solid. The solid was taken up in DCM and triturated with Et₂Oto give a solid which was collected by filtration and dried under vacuumto give the title compound (130 mg, 27%) as a yellow solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.38-0.40 (2H, m), 0.45-0.49 (2H, m),1.66-1.70 (1H, m), 2.66 (4H, t), 3.71 (4H, t), 3.75 (6H, s), 5.08 (2H,s), 5.84 (1H, s), 6.45 (1H, s), 6.59 (2H, s), 8.33 (1H, s), 8.72 (1H,s), 10.80 (1H, s), 11.35 (1H, s). MS: m/z 480 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.003 μM.

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamideused as starting material was prepared as follows:—

Trimethylaluminium (2M in toluene, 7.44 ml, 14.88 mmol) was addeddropwise to a stirred suspension of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl (1.70 g, 5.95mmol) and methyl 5-chloropyrazine-2-carboxylate (1.03 g, 5.95 mmol) inanhydrous toluene (29.8 ml) at ambient temperature. The resultingsolution was then stirred under nitrogen at ambient temperature for 18h. The reaction mixture was quenched with methanol (5 mL) and HCl (2Maqueous solution), diluted with water (200 mL) and extracted with EtOAc(3×150 mL). The organics were washed with water (200 mL), brine (200 mL)dried over MgSO₄, filtered and concentrated. On evaporation aprecipitate was formed which was collected by filtration, washed withMeOH (20 mL) and air dried to afford the desired compound (1.65 g, 71%)as an orange solid, which was used without further purification.

1H NMR (500.13 MHz, DMSO-d6, 373K) δ 3.78 (6H, s), 5.12 (2H, s), 5.94(1H, s), 6.46 (1H, s), 6.62 (2H, s), 8.87 (1H, s), 9.09 (1H, s), 10.99(1H, s), 11.24 (1H, s). MS: m/z 390 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.060 μM.

Example 110N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]benzamide

N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]benzamidewas prepared following the procedure for Example 100, but starting fromethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (0.276 g, 1.00mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.249 g,1 mmol) and a 2M solution of trimethylaluminium in toluene (1.25 mL, 2.5mmol). The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (0.027 g, 5.63%) as a white solid.

1HNMR (500.133 MHz, DMSO-d6+CD3COOD) δ: 1.13 (6H, d), 2.31 (3H, s),2.60-2.68 (2H, m), 3.19 (2H, s), 3.70 (1H, s), 3.65 (6H, s), 5.08 (2H,s), 5.68 (1H, s), 6.40-6.44 (1H, m), 6.58 (2H, s), 6.97 (2H, d), 7.82(2H, d). MS: m/z 480 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00068 μM.

Ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate used as startingmaterial was prepared as follows:—

Titanium (IV) isopropoxide (2.99 mL, 10.00 mmol) was added to ethyl4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (1.312 g, 5.00 mmol) andformaldehyde (0.601 g, 20.00 mmol) in ethanol (25 mL) warmed to 60° C.over a period of 45 mins under nitrogen. The resulting solution wascooled to 20° C. and sodium borohydride (0.473 g, 12.50 mmol) was addedin one portion and the suspension stirred at 60° C. for 18 h. Thereaction was quenched with ammonia (2 ml). The solid filtered off andwashed with 10% MeOH in DCM (2×50 ml). The organic layer was evaporatedto dryness and the crude product purified by silica columnchromatography, eluting with a gradient of 0 to 5% MeOH in DCMcontaining 0.1% ammonia. Fractions were evaporated to dryness to affordan oil. This was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thedesired compound (0.320 g, 23.16%) as a white crystalline solid.

1H NMR (399.9 MHz, CDCl3) δ 1.11 (6H, d), 1.29 (3H, t), 2.24 (3H, s),2.25-2.30 (2H, m), 2.59 (1H, d), 2.62 (1H, d), 3.53-3.57 (2H, m), 4.26(2H, q), 6.75-6.79 (2H, m), 7.82-7.86 (2H, m). MS: m/z 277 (MH+).

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, used as startingmaterial was prepared as in Example 100.

Example 111N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide

A 2M solution of trimethylaluminium in toluene (0.691 mL, 1.38 mmol) wasadded dropwise to a stirred solution of ethyl4-(3,3-dimethylpiperazin-1-yl)benzoate (145 mg, 0.55 mmol) and5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (138 mg, 0.55 mmol)in toluene (5 mL) at 20° C., over a period of 5 mins under nitrogen. Theresulting solution was stirred at 20° C. for 24 h. This was diluted withacetone (25 ml) and an excess of damp solid sodium sulphite was added.The mixture was stirred for 1 h and the solid filtered off. The solidwas washed with 10% MeOH/DCM and the combined organics evaporated todryness. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (27.0 mg, 10.49%) as a colourlessgum.

1HNMR (500.13 MHz, DMSO-d6 @ 373K) δ: 1.11 (6H, s), 2.85-2.91 (2H, m),3.03 (2H, s), 3.18-3.22 (2H, m), 3.78 (6H, s), 5.09 (2H, s), 5.62 (1H,s), 6.44 (1H, t), 6.60 (2H, s), 6.92 (2H, d), 7.82 (2H, d), 10.19 (1H,s), 11.12 (1H, s). MS: m/z 466 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00076 μM.

Ethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate used as starting materialwas prepared as follows:—

Ethyl 4-fluorobenzoate (0.151 mL, 1 mmol), 2,2-dimethylpiperazine (0.137g, 1.20 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.349 mL, 2.00mmol) were dissolved in DMA (2 mL) and sealed into a microwave tube. Thereaction was heated to 200° C. for 4 h in the microwave reactor andcooled to room temperature. The crude mixture was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 3.5M ammonia in methanol, fractions wereevaporated to dryness to afford an oil. The crude product was purifiedby silica column chromatography, eluting with a gradient of 0 to 10% 2Mammonia/MeOH in DCM. Pure fractions were evaporated to dryness to affordethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate (0.145 g, 55.3%) as a whitesolid. 1H NMR (399.9 MHz, CDCl3) δ 1.15 (6H, d), 1.37 (3H, t), 2.38 (1H,d), 2.41 (1H, d), 2.96-3.04 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q),6.84-6.87 (2H, m), 7.89-7.93 (2H, m). MS: m/z 266 (MH+).

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, used as startingmaterial was prepared as in Example 100.

Example 112N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrazine-2-carboxamide

(2S,6R)-2,6-Dimethylpiperazine (228 mg, 2.00 mmol) was added in oneportion to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(388 mg, 1.00 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C.The resulting solution was stirred at 100° C. for 18 h. The crudeproduct was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHto afford impure material. The concentrated eluent was purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (164 mg, 35%) asa cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.05-1.06 (6H, d), 2.43-2.50 (2H, m),2.72-2.78 (2H, m), 2.88 (4H, s), 3.72 (6H, s), 4.39 (2H, d), 6.33 (1H,t), 6.42 (2H, d), 6.46 (1H, s), 8.34 (1H, d), 8.69 (1H, d), 9.73 (1H,s), 12.18 (1H, s), no NH observed. MS: m/z 466 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0017 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 1135-(4-Cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(388 mg, 1.00 mmol) was added in one portion to 1-cyclopropylpiperazine,2HCl (398 mg, 2.00 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.52ml, 3.00 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. Theresulting solution was stirred at 100° C. for 18 h. The crude productwas purified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH to affordimpure material. The concentrated eluent was purified by preparativeHPLC, using decreasingly polar mixtures of water (containing 1% NH3) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the title compound (45 mg, 9%) as acream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.39 (2H, t), 0.46-0.48 (2H, m), 1.67-1.70(1H, m), 2.66 (4H, q), 2.88 (4H, s), 3.69-3.72 (4H, m), 3.72 (6H, s),6.33 (1H, t), 6.42 (2H, d), 6.46 (1H, s), 8.35 (1H, d), 8.71 (1H, d),9.76 (1H, s), 12.18 (1H, s). MS: m/z 478 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0023 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 1145-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

1,2,3,4,6,7,8,8a-Octahydropyrrolo[1,2-a]pyrazine (429 mg, 3.40 mmol) wasadded in one portion to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(659 mg, 1.70 mmol) in anhydrous dimethylsulfoxide (1.70 ml) at 25° C.The resulting solution was stirred at 100° C. for 18 h. The crudeproduct was purified by ion exchange chromatography, using a SCX column.The desired product was eluted from the column using 7M NH3/MeOH toafford impure material. The concentrated eluent was purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% TFA) and MeCN as eluents. The material was then put through basicHPLC to obtain the free base. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (438 mg, 54%) asa cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.35-1.45 (1H, m), 1.63-1.80 (2H, m),1.82-1.91 (1H, m), 1.93-2.01 (1H, m), 2.09 (1H, q), 2.16-2.20 (1H, m),2.70-2.76 (1H, m), 2.88 (4H, s), 3.04-3.11 (3H, m), 3.72 (6H, s), 4.47(1H, d), 4.63 (1H, d), 6.33 (1H, t), 6.42 (2H, d), 6.47 (1H, s), 8.36(1H, d), 8.71 (1H, d), 9.76 (1H, s), 12.18 (1H, s). MS: m/z 478 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0016 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 1155-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(585 mg, 1.50 mmol) was added in one portion to2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, HCl (530 mg, 3.00mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (1.04 ml, 6.00 mmol) inanhydrous dimethylsulfoxide (1.50 ml) at 25° C. The resulting solutionwas stirred at 100° C. for 18 h. The crude product was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH to afford impure material. Theconcentrated eluent was purified by preparative HPLC, using decreasinglypolar mixtures of water (containing 1% NH3) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford the title compound (302 mg, 41%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.21-1.29 (2H, m), 1.49-1.67 (1H, m),1.60-1.64 (2H, m), 1.74 (1H, d), 1.90 (1H, t), 1.93-2.00 (1H, m),2.10-2.17 (1H, m), 2.67-2.73 (1H, m), 2.82 (2H, d), 3.06-3.13 (1H, m),3.75 (6H, s), 4.38 (1H, d), 4.46 (1H, d), 5.08 (2H, s), 5.84 (1H, s),6.44 (1H, s), 6.59 (2H, d), 8.34 (1H, s), 8.71 (1H, s), 10.79 (1H, s),11.35 (1H, s). MS: m/z 494 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0023 μM.

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as outlined in Example 109.

Example 1164-(4-cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide

4-(4-Cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamidewas prepared following the procedure as outlined for Example 100,starting from ethyl 4-(4-cyclopropylpiperazin-1-yl)benzoate (0.329 g,1.2 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-aminehydrochloride (0.343 g, 1.20 mmol) and 2M trimethylaluminium in toluene(1.500 mL, 3.00 mmol). The crude product was purified by preparativeHPLC, using decreasingly polar mixtures of water (containing 1% NH3) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the title compound (0.022 g, 3.84%) as awhite solid. 1H NMR (500.13 MHz, DMSOd6) δ 0.34-0.40 (2H, m), 0.45-0.50(2H, m), 1.67-1.75 (1H, m), 2.67-2.73 (4H, m), 3.24-3.32 (4H, m), 3.78(6H, s), 5.08 (2H, s), 5.68 (1H, s), 6.42-6.46 (1H, m), 6.58-6.61 (2H,m), 6.95 (2H, d), 7.83 (2H, d), 10.30 (1H, s), 11.01 (1H, s). MS: m/z478 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00093 μM.

Ethyl 4-(4-cyclopropylpiperazin-1-yl)benzoate used as starting materialwas prepared following the procedure as outlined for ethyl4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (Example 100), startingfrom ethyl 4-fluorobenzoate (0.880 mL, 6 mmol) and1-cyclopropylpiperazine (1.666 g, 13.20 mmol) in DMSO (15 mL) The crudeproduct was purified by silica column chromatography, eluting with agradient of 0 to 8% 2.5M ammonia/MeOH in DCM. Pure fractions wereevaporated to dryness to afford the desired compound (1.405 g, 85%) as abeige solid.

1H NMR (399.9 MHz, CDCl3) δ 0.43-0.52 (4H, m), 1.34-1.39 (3H, m),1.63-1.68 (1H, m), 2.75 (4H, t), 3.29 (4H, t), 4.32 (2H, q), 6.84-6.88(2H, m), 7.90-7.97 (2H, m). MS: m/z 275 (MH+).

1-Cyclopropylpiperazine used as starting material was prepared asfollows: 1-Cyclopropylpiperazine dihydrochloride (1.493 g, 7.5 mmol) wasdissolved in water (5.00 mL) and methanol (5.00 mL) and converted to itsfreebase by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 3.5M ammonia inmethanol and pure fractions were evaporated to dryness to afford1-cyclopropylpiperazine (0.796 g, 84%) as an oil.

1H NMR (399.9 MHz, CDCl3) δ 0.31-0.39 (4H, m), 1.51-1.56 (1H, m),1.63-1.67 (1H, m), 2.51 (4H, s), 2.77 (4H, t).

1-Cyclopropylpiperazine dihydrochloride was prepared as follows:—

4.0M HCl in dioxane (42.7 mL, 170.78 mmol) was added to a stirredsolution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (7.73 g,34.16 mmol) in a mixture of methanol (50.0 mL) and ethyl acetate (200mL). The resulting suspension was stirred at room temperature for 24 hunder nitrogen. The white solid filtered off to give1-cyclopropylpiperazine dihydrochloride (6.30 g, 93%).

1H NMR (399.9 MHz, DMSO-d6) δ 0.73-0.86 (2H, m), 1.07-1.18 (2H, m),2.85-2.99 (1H, m), 3.30-3.40 (4H, m), 3.52-3.65 (4H, m), 9.89 (2H, s),11.99 (1H, s).

tert-Butyl 4-cyclopropylpiperazine-1-carboxylate was prepared asfollows:—

A solution of tert-butyl piperazine-1-carboxylate (9.31 g, 50 mmol),[(1-ethoxycyclopropyl)oxy]trimethylsilane (20.11 mL, 100.00 mmol) andacetic acid (14.31 mL, 250.00 mmol) in tetrahydrofuran (100 mL),methanol (10 mL) was treated with sodium cyanoborohydride (4.71 g, 75.00mmol) at 20° C. The resulting solution was stirred at 60° C. for 18 h.The reaction mixture was cooled, filtered and evaporated to dryness. 1NHCl (40 ml) and water (60 ml) were added and the solution extracted withethyl acetate (3×50 ml). The aqueous layer was basified to pH 10 withsolid potassium carbonate and extracted with ethyl acetate (4×50 ml).The organic extracts were washed with saturated sodium chloride solution(50 ml) and dried over MgSO₄, filtered and evaporated to dryness to givetert-butyl 4-cyclopropylpiperazine-1-carboxylate (7.73 g, 68.3%) as awhite waxy solid.

¹H NMR (399.9 MHz, CDCl3) δ 0.33-0.40 (4H, m), 1.39 (9H, s), 1.52-1.55(1H, m), 2.48 (4H, t), 3.31 (4H, t).

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as in Example 12.

Example 117N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-4-oxidopiperazin-4-ium-1-yl)benzamide

3-Chloroperoxybenzoic acid (129 mg, 0.53 mmol) was added in one portiontoN-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(225 mg, 0.50 mmol) in acetone (15 mL) at ambient temperature. Theresulting solution was stirred at ambient temperature for 2 h. Thereaction mixture was concentrated onto silica and the crude product waspurified by silica column chromatography, eluting with a gradient of 0to 10% 7M NH3/MeOH in DCM to 100% methanol. The residue was furtherpurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford the title compound (183 mg, 79%) as acream solid.

1H NMR (700.034 MHz, DMSO) δ 2.85 (4H, s), 2.94 (2H, d), 3.09 (3H, s),3.44 (2H, td), 3.53 (2H, td), 3.65 (2H, d), 3.70 (6H, s), 6.31 (1H, t),6.37 (1H, s), 6.40 (2H, d), 7.00 (2H, d), 7.90 (2H, d), 10.37 (1H, s),12.00 (1H, s). MS: m/z 466 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0013 μM.

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamidewas prepared as outlined in Example 10.

Example 1184-(4-Cyclobutylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide

4-(4-Cyclobutylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamidewas prepared following the procedure as outlined for Example 100,starting from 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.173g, 0.69 mmol), ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (0.2 g, 0.69mmol) and a 2M solution of trimethylaluminium in toluene (1.387 mL, 2.77mmol) in toluene (10 ml) at room temperature for 20 h. The reactionmixture was poured into acetone (20 mL), quenched with excess dampsodium sulphite, filtered and evaporated to afford a yellow solid.Acetonitrile (10 ml) was added and this was filtered to afford the titlecompound (0.079 g, 23.17%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.63-1.66 (1H, m), 1.67-1.70 (1H, m),1.78-1.89 (2H, m), 1.97-2.03 (2H, m), 2.38 (4H, t), 2.75 (1H, t), 3.75(6H, s), 5.08 (2H, s), 5.58 (1H, s), 6.45 (1H, s), 6.60-6.60 (2H, m),7.01 (2H, d), 7.86 (2H, d), 10.61 (1H, s), 11.49 (1H, s).

MS: m/z 492 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0011 μM.

Ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate used as starting materialwas prepared as follows:

Ethyl 4-fluorobenzoate (0.753 g, 4.48 mmol) was added to a solution of1-cyclobutylpiperazine (0.571 g, 4.07 mmol) and potassium carbonate(0.563 g, 4.07 mmol) in DMSO (8 mL) under nitrogen. The resultingsolution was stirred at 100° C. for 18 h and evaporated to dryness. Theresidue was triturated with diethyl ether, filtered, and evaporated andthe crude product was purified by silica column chromatography, elutingwith a gradient of 0 to 2.5% 2.5N MeOH in DCM. Pure fractions wereevaporated to dryness to afford ethyl4-(4-cyclobutylpiperazin-1-yl)benzoate (0.387 g, 32.9%) as a whitesolid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.28-1.32 (3H, t), 1.62-1.70 (2H, m),1.77-1.88 (2H, m), 1.95-2.04 (2H, m), 2.35-2.39 (4H, t), 2.70-2.78 (1H,m), 3.28-3.32 (4H, t), 4.22-4.27 (2H, m), 6.96-6.98 (2H, d), 7.66-7.80(2H, d). MS: m/z 289 (MH+).

1-Cyclobutylpiperazine used as starting material was prepared asfollows:

Water (0.15 mL), cyclobutanone (1 g, 14.27 mmol) and acetic acid (1.742mL, 30.44 mmol) were added to a stirred solution of tert-butylpiperazine-1-carboxylate (1.772 g, 9.51 mmol) in THF (20 mL) undernitrogen. Sodium cyanoborohydride (0.897 g, 14.27 mmol) was addedportion wise over a period of 10 mins. The resulting mixture was stirredat 60° C. for 20 h. The reaction mixture was evaporated to dryness andmixed with water (40 mL) and 1M HCl (15 mL). The solution was washedwith EtOAc (2×25 mL), basified with solid K₂CO₃ and extracted with EtOAc(2×15 mL). The organic layer was washed with saturated brine and driedover MgSO₄, filtered and evaporated to afford pure tert-butyl4-cyclobutylpiperazine-1-carboxylate (1.155 g, 50.5%) as a colourlessoil.

1H NMR (399.9 MHz, DMSO-d6) δ 1.40 (9H, s), 1.62-1.65 (2H, m), 1.75-1.80(2H, m), 1.92-1.98 (2H, m), 2.17 (4H, t), 2.68 (1H, t), 3.28-3.30 (4H,s).

A solution of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (1.1553 g,4.81 mmol) in ethyl acetate (10 mL) and methanol (10.00 mL) was treatedwith a 4M-solution hydrogen chloride in dioxane (1.669 mL, 48.07 mmol)was stirred at room temperature for 40 h under nitrogen. The reactionwas incomplete so f 4M-solution hydrogen chloride in dioxane (10 mL) wasadded and the solution was stirred at room temperature for a further 2h. The reaction mixture was evaporated to dryness to afford a solid. Thecrude product was purified by ion exchange chromatography, using a SCXcolumn. The desired product was eluted from the column using 3.5MNH3/MeOH and pure fractions were evaporated to dryness to afford1-cyclobutylpiperazine (0.571 g, 85%) as a yellow oil.

1H NMR (399.9 MHz, DMSO-d6) δ 1.64 (2H, s), 1.74-1.75 (2H, m), 1.92 (2H,s), 2.14 (4H, s), 2.63-2.66 (4H, m), 3.18 (1H, s).

Example 1192-(1,3,4,6,7,8,9,9a-Octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 2.15 mL, 4.30 mmol) was addeddropwise to a stirred suspension of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl (491 mg, 1.72mmol) and methyl2-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate(475 mg, 1.72 mmol) in toluene (8.6 mL) at 25° C. The resulting solutionwas stirred at ambient temperature for 18 h and then at 60° C. for 2 h.The reaction mixture was cautiously quenched with methanol (20 mL) andtreated with HCl (2N aqueous solution, until a freely stirred solutionwas obtained). The crude product was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and evaporated to dryness to afford crudeproduct. The impure material was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 0.1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (361 mg, 43%) as a solid.

1H NMR (500.13 MHz, DMSO-d6, 373K) δ 1.21-1.27 (1H, m), 1.28-1.35 (1H,m), 1.52-1.59 (1H, m), 1.59-1.64 (2H, m), 1.76 (1H, d), 1.85-1.91 (1H,m), 1.98-2.03 (1H, m), 2.10-2.15 (1H, m), 2.68-2.73 (1H, m), 2.80-2.84(2H, m), 3.08-3.13 (1H, m), 3.78 (6H, s), 4.57-4.61 (1H, m), 4.67-4.71(1H, m), 5.11 (2H, s), 5.70 (1H, s), 6.46 (1H, t), 6.62 (2H, d), 8.86(2H, s), 10.30 (1H, s), 11.30 (1H, s). MS: m/z 494 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0033 μM.

Methyl2-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylatewas prepared as outlined in Example 127.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl was prepared asoutlined in Example 12.

Example 1205-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]thiophene-2-carboxamide

2M Trimethylaluminium (1.525 ml, 3.05 mmol) in toluene, was addeddropwise to a stirred solution of ethyl5-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)thiophene-2-carboxylate(0.342 g, 1.22 mmol) and5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.302 g, 1.22 mmol)in toluene (8.71 ml) at 20° C. under nitrogen. The reaction mixture wasstirred at ambient temperature for 18 h and then stirred and heated at65° C. for 20 h. Ethyl acetate (5 mL) was added carefully to thereaction mixture followed by a solution of potassium sodium tartrate (5mL, 20% aqueous). More ethyl acetate (50 mL) and water (25 mL) was addedand the mixture was filtered through celite. The filtrate wastransferred to a separating funnel and the aqueous layer removed. Theethyl acetate layer was washed with saturated brine and then dried overmagnesium sulphate. After filtration the solvent was evaporated to givethe crude product as a yellow gum, 640 mg. The crude product waspurified by preparative HPLC, using decreasingly polar mixtures of water(containing 1% TFA) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the TFA salt ofthe product. This was dissolved in methanol and purified by ion exchangechromatography, using a SCX2 column. The desired product was eluted fromthe column using 2M NH3 in methanol and pure fractions were evaporatedto dryness then triturated with acetonitrile to afford the titlecompound (0.174 g, 29.6%) as a solid.

1H NMR (500.13 MHz, DMSO-d6, CD3CO2D) δ 1.41-1.43 (1H, m), 1.73-1.78(2H, m), 1.87-1.91 (2H, m), 2.16-2.23 (2H, m), 2.34-2.38 (1H, m),2.68-2.72 (1H, m), 2.89 (4H, s), 3.00-3.08 (3H, m), 3.50-3.53 (1H, m),3.66-3.69 (1H, m), 3.74 (6H, d), 6.12 (1H, d), 6.25 (1H, s), 6.33 (1H,t), 6.41 (2H, d), 7.70 (1H, t); MS: m/z 482 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00098 μM.

Ethyl5-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)thiophene-2-carboxylate,used as starting material was prepared as follows:

Palladium(II) acetate (0.112 g, 0.50 mmol) was added to ethyl5-bromothiophene-2-carboxylate (1.175 g, 5 mmol),1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (0.631 g, 5.00 mmol),rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) andcesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C.under nitrogen. The resulting suspension was stirred at 110° C. for 23h. The mixture was filtered through celite washing through with ethylacetate and the filtrate was evaporated to dryness to give a brown oil.The crude product was purified by ion exchange chromatography, using aSCX2 column. The crude material was dissolved in methanol and thenapplied to the column. The desired product was eluted from the columnusing 2M NH3 in methanol and pure fractions were evaporated to drynessto afford the crude product as a brown solid. This material was furtherpurified by silica column chromatography, eluting with a gradient of 0to 4% MeOH in DCM. Pure fractions were evaporated to dryness to affordthe desired compound (0.727 g, 51.9%) as a white solid.

1H NMR (399.9 MHz, CDCl3) δ 1.33 (3H, t), 1.43-1.53 (1H, m), 1.63 (1H,s), 1.73-1.93 (3H, m), 2.10-2.22 (2H, m), 2.33-2.40 (1H, m), 2.74 (1H,t), 3.07-3.16 (3H, m), 3.51-3.55 (1H, m), 3.67-3.71 (1H, m), 4.28 (2H,q), 6.01 (1H, d), 7.55 (1H, d)

MS: m/z 281 (MH+)

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 1215-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]thiophene-2-carboxamide

2M Trimethylaluminium (1.525 ml, 3.05 mmol) in toluene, was addeddropwise to a stirred solution of ethyl5-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)thiophene-2-carboxylate(0.342 g, 1.22 mmol) and5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.304 g, 1.22 mmol)in toluene (8.71 ml) at 20° C. under nitrogen. The reaction mixture wasstirred at room temperature for 18 h and then heated at 65° C. for 6 h.

Ethyl acetate (5 mL) was added to the reaction mixture followed by asolution of potassium sodium tartrate (5 mL, 20% aqueous). More ethylacetate (50 mL) and water (25 mL) was added and the mixture was filteredthrough celite. The filtrate was transferred to a separating funnel andthe aqueous layer removed. The ethyl acetate layer was washed withsaturated brine and then dried over magnesium sulphate. After filtrationthe solvent was evaporated to give the crude product as a yellow gum.The crude product was purified by preparative LCMS, using decreasinglypolar mixtures of water (containing 1% TFA) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford the TFA salt of the product. This was dissolved in methanol andpurified by ion exchange chromatography, using a SCX2 column. Thedesired product was eluted from the column using 2M NH3 in methanol andpure fractions were evaporated to dryness then triturated with ethanolto afford the title compound (0.266 g, 45.1%) as a white solid.

1H NMR (500.13 MHz, DMSO-d6, CD3CO2D) δ 1.40-1.44 (1H, m), 1.72-1.80(2H, m), 1.85-1.90 (2H, m), 2.17-2.22 (2H, m), 2.34-2.39 (1H, m), 2.73(1H, t), 3.03-3.09 (3H, m), 3.52-3.54 (1H, m), 3.67-3.70 (1H, m), 3.77(6H, s), 5.09 (2H, s), 5.62 (1H, s), 6.16 (1H, d), 6.45 (1H, t), 6.60(2H, d), 7.64 (1H, d); MS: m/z 484 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00079 μM.

Ethyl5-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)thiophene-2-carboxylateis prepared as outlined in Example 120.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, used as startingmaterial was prepared as in Example 100.

Example 1225-(3,4,6,7,8,8a-Hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(585 mg, 1.50 mmol) was added in one portion to1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (379 mg, 3.00 mmol) inanhydrous dimethylsulfoxide (1.50 ml) at 25° C. The resulting solutionwas stirred at 100° C. for 18 h. The residue was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH to afford impure material. Theconcentrated eluent was purified by preparative HPLC, using decreasinglypolar mixtures of water (containing 1% NH3) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford impure product as a yellow solid. The impure material was thenrepurified by silica column chromatography, eluting with a gradient of 0to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness toafford the title compound (269 mg, 37%) as a yellow solid.

1H NMR (500.133 MHz, DMSO, 373K) δ 1.38-1.46 (1H, m), 1.67-1.82 (2H, m),1.85-1.91 (1H, m), 2.04-2.10 (1H, m), 2.17 (1H, q), 2.22-2.29 (1H, m),2.78 (1H, dd), 3.02-3.16 (3H, m), 3.76 (6H, s), 4.41 (1H, d), 4.57 (1H,d), 5.09 (2H, s), 5.85 (1H, s), 6.44 (1H, s), 6.59 (2H, d), 8.26 (1H,d), 8.71 (1H, s), 10.42 (1H, s), 11.13 (1H, s). MS: m/z 480 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0013 μM.

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 109.

Example 123N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3,4-dimethylpiperazin-1-yl)pyrazine-2-carboxamide

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(388 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine(228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C.The resulting solution was stirred at ambient temperature for 2 h. Theresidue was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHto afford impure material. The concentrated eluent was purified bysilica column chromatography, eluting with a gradient of 0 to 10% 7MNH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford thetitle compound (375 mg, 81%) as a yellow solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.07-1.09 (3H, d), 2.06-2.20 (2H, m), 2.23(3H, s), 2.76-2.86 (2H, m), 2.87 (4H, s), 3.13-3.19 (1H, m), 3.72 (6H,s), 4.27-4.30 (2H, m), 6.33 (1H, t), 6.42 (2H, d), 6.46 (1H, s), 8.35(1H, d), 8.70 (1H, d), 9.75 (1H, s), 12.18 (1H, s). MS: m/z 466 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0022 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 124N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(3,4-dimethylpiperazin-1-yl)pyrazine-2-carboxamide

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(390 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine(228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C.The resulting solution was stirred at ambient temperature for 2 h. Theresidue was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHto afford impure material. The concentrated eluent was purified bysilica column chromatography, eluting with a gradient of 0 to 10% 7MNH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford thetitle compound (392 mg, 84%) as a yellow solid.

1H NMR (399.902 MHz, DMSO) δ 1.08 (3H, d), 2.06-2.12 (1H, m), 2.18 (1H,td), 2.23 (3H, s), 2.77-2.88 (2H, m), 3.14-3.21 (1H, m), 3.75 (6H, s),4.32 (2H, t), 5.08 (2H, s), 5.84 (1H, s), 6.44 (1H, t), 6.59 (2H, d),8.34 (1H, s), 8.71 (1H, s), 10.79 (1H, s), 11.35 (1H, s). MS: m/z 468(MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0015 μM.

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as outlined in Example 109.

Example 125N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrazine-2-carboxamide

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(271 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of(2R,6S)-1,2,6-trimethylpiperazine and2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol)in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 2 h. The reaction wasincomplete and N-ethyl-N-propan-2-ylpropan-2-amine (0.24 ml, 1.40 mmol)was added and the solution was stirred at 60° C. for a further 2 h. Thereaction mixture was diluted with methanol (20 mL) and purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH to afford impure material. Theconcentrated eluent was purified by silica column chromatography,eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractionswere evaporated to dryness to afford the title compound (246 mg, 73%) asa yellow solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.10-1.12 (6H, d), 2.15-2.21 (2H, m), 2.20(3H, s), 2.75 (2H, t), 2.88 (4H, s), 3.72 (6H, s), 4.37 (2H, d), 6.33(1H, s), 6.42-6.43 (2H, m), 6.46 (1H, s), 8.37 (1H, s), 8.70 (1H, s),9.75 (1H, s), 12.18 (1H, s). MS: m/z 480 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0017 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile used as startingmaterial was prepared as follows;—

Macroporous triethylammonium methylpolystyrene cyanoborohydride (2.31mmol/g, 5.05 g, 11.67 mmol) was added tocis-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.00 g,4.67 mmol), 37% aqueous formaldehyde (6.99 ml, 93.33 mmol) and aceticacid (0.53 ml, 9.33 mmol) in methanol (9.33 ml) at 25° C. The resultingsuspension was stirred under nitrogen at ambient temperature for 24 h.The macroporous triethylammonium methylpolystyrene cyanoborohydride wasremoved by filtration, washing with methanol (50 mL). The filtrate waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness.

The residue was taken up in ethyl acetate (21.00 mL) and methanol (10.00mL) and treated with hydrogen chloride (4M in 1,4-dioxane, 4.21 ml,16.84 mmol) at 25° C. under nitrogen. The resulting solution was stirredat ambient temperature for 3 days. The crude product was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH and evaporated to dryness toafford a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (645 mg, quant.) as acolourless oil. This was used directly with no further purification.

Example 1262-(4-cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.92 mL, 3.85 mmol) was addeddropwise to a stirred suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (381 mg, 1.54 mmol)and methyl 2-(4-cyclopropylpiperazin-1-yl)pyrimidine-5-carboxylate (404mg, 1.54 mmol) in toluene (7.7 mL) at 25° C. The resulting solution wasstirred at ambient temperature for 18 h and then heated at 60° C. for 2h. The reaction mixture was quenched with methanol (20 mL) and treatedwith HCl (2N aqueous solution). The crude product was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH and evaporated to dryness toafford impure product. The impure material was purified by preparativeHPLC, using decreasingly polar mixtures of water (containing 0.1% NH3)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the title compound (100 mg, 14%) as asolid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.36-0.41 (2H, m), 0.45-0.47 (2H, m),1.65-1.68 (1H, m), 2.61 (4H, t), 2.88 (4H, s), 3.72 (6H, s), 3.80 (4H,t), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 8.90 (2H, s), 10.60 (1H,s), 12.14 (1H, s). MS: m/z 478 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0036 μM.

Methyl 2-(4-cyclopropylpiperazin-1-yl)pyrimidine-5-carboxylate used asstarting material was prepared as follows;13

A solution of methyl-2-chloropyrimidine-5-carboxylate (900 mg, 5.22mmol) in dichloromethane (7.50 ml) was added to a stirred suspension of1-cyclopropylpiperazine, 2HCl (1038 mg, 5.22 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (4.10 mL, 23.47 mmol) indichloromethane (13 mL) at room temperature under nitrogen. Theresulting solution was stirred at ambient temperature for 18 h. Thereaction mixture was poured onto ice (100 mL), extracted withdichloromethane (3×75 mL), the organic layer was dried over MgSO₄,filtered and evaporated to afford white solid. The crude product waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH and purefractions were evaporated to dryness to afford the desired compound (880mg, 64%) as a white solid. This was used directly with no furtherpurification.

1H NMR (399.9 MHz, DMSO-d6) δ 0.36-0.39 (2H, m), 0.45-0.47 (2H, m),1.65-1.68 (1H, m), 2.61 (4H, t), 3.81 (3H, s), 3.81-3.84 (4H, t), 8.79(2H, s). MS: m/z 263 (MH+).5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 1272-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.45 mL, 2.90 mmol) was addeddropwise to a stirred suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (286 mg, 1.16 mmol)and methyl2-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate(320 mg, 1.16 mmol) in toluene (5.8 mL) at 25° C. The resulting solutionwas stirred at ambient temperature for 18 h and then at 60° C. for 2 h.The reaction mixture was quenched with methanol (20 mL) and treated withHCl (2N aqueous solution, until a freely stirred solution was obtained).The crude product was purified by ion exchange chromatography, using anSCX column. The desired product was eluted from the column using 7MNH3/MeOH and evaporated to dryness to afford impure product. The impurematerial was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (238 mg, 42%) as a solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.14-1.32 (2H, m), 1.46-1.55 (1H, m), 1.61(2H, d), 1.73 (1H, d), 1.80-1.83 (1H, m), 1.92-1.99 (1H, m), 2.03-2.10(1H, m), 2.64-2.70 (1H, m), 2.79 (2H, d), 2.88 (4H, s), 3.02-3.09 (1H,m), 3.72 (6H, s), 4.55-4.59 (1H, m), 4.65-4.68 (1H, m), 6.33 (1H, t),6.42 (2H, d), 6.44 (1H, s), 8.89 (2H, s), 10.59 (1H, s), 12.15 (1H, s).MS: m/z 492 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0029 μM.

Methyl2-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylateused as starting material was prepared as follows;—

A solution of methyl 2-chloropyrimidine-5-carboxylate (900 mg, 5.22mmol) in dichloromethane (7.50 ml) was added to a stirred suspension of2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, HCl (1106 mg, 6.26mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (3.19 mL, 18.25 mmol) indichloromethane (13.00 mL) at room temperature under nitrogen. Theresulting solution was stirred at ambient temperature for 18 h. Thereaction mixture was poured onto ice (50 mL), extracted with DCM (3×50mL), the organic layer was dried over MgSO₄, filtered and evaporated toafford yellow solid. The crude product was purified by crystallisationfrom IPA to afford the title compound (591 mg, 41%) as a white solid.The filtrate still contained some product and was purified by silicacolumn chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOHin dichloromethane. Pure fractions were evaporated to dryness to afforda further sample of the title compound (402 mg, 28%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.14-1.30 (2H, m), 1.46-1.55 (1H, m), 1.61(2H, d), 1.72 (1H, d), 1.81 (1H, t), 1.95 (1H, m), 2.06 (1H, m),2.67-2.70 (1H, m), 2.80 (2H, d), 3.05-3.12 (1H, m), 3.81 (3H, s), 4.59(1H, m), 4.68 (1H, d), 8.79 (2H, s). MS: m/z 277 (MH+).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 1282-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 2.55 ml, 5.10 mmol) was addeddropwise to a stirred suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (504 mg, 2.04 mmol)and methyl2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate(535 mg, 2.04 mmol) in toluene (10.20 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 18 h and then at 60° C.for 2 h. The reaction mixture was quenched with methanol (20 mL) andtreated with HCl (2N aqueous solution, until a freely stirred solutionwas obtained). The crude product was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and evaporated to dryness to afford impureproduct. The impure material was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 0.1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (288 mg, 30%) as a solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.36-1.40 (1H, m), 1.68-1.75 (2H, m),1.83-1.90 (2H, m), 2.07 (2H, q), 2.67-2.72 (1H, m), 2.88 (4H, s),3.01-3.08 (3H, m), 3.72 (6H, s), 4.71-4.75 (1H, m), 4.87 (1H, d), 6.33(1H, t), 6.42 (2H, d), 6.44 (1H, s), 8.90 (2H, s), 10.59 (1H, s), 12.15(1H, s). MS: m/z 478 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.003 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylateused as starting material was prepared as follows;—

A solution of methyl 2-chloropyrimidine-5-carboxylate (1.56 g, 9.04mmol) in dichloromethane (7.50 ml) was added to a stirred suspension of1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (1.37 g, 10.85 mmol)and N-ethyl-N-propan-2-ylpropan-2-amine (3.95 ml, 22.60 mmol) indichloromethane (22.60 ml) at room temperature under nitrogen. Theresulting solution was stirred at ambient temperature for 18 h. Thereaction mixture was poured onto ice (100 mL), extracted withdichloromethane (3×100 mL), the organic layer was dried over MgSO₄,filtered and evaporated to afford a yellow solid. The aqueous layer waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford crude product. The combined crudeproduct was purified by silica column chromatography, eluting with agradient of 0 to 10% 7M NH3/MeOH in dichloromethane. Pure fractions wereevaporated to dryness to afford the desired compound (1.36 g, 57%) as ayellow solid.

1H NMR (399.902 MHz, DMSO) δ 1.33-1.44 (1H, m), 1.63-1.78 (2H, m),1.80-1.93 (2H, m), 2.04-2.11 (2H, m), 2.72 (1H, dd), 3.00-3.09 (3H, m),3.81 (3H, s), 4.74 (1H, d), 4.88 (1H, d), 8.79 (2H, s). MS: m/z 263(MH+).

Example 129

5-[(3R,5S)-4-(cyanomethyl)-3,5-dimethylpiperazin-1-yl]-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(271 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of(2R,6S)-1,2,6-trimethylpiperazine and2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol)in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 2 h. The reaction wasincomplete and N-ethyl-N-propan-2-ylpropan-2-amine (0.24 ml, 1.40 mmol)was added and the solution was stirred at 60° C. for a further 2 h. Thereaction mixture was diluted with methanol (20 mL) and purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH to afford impure material. Theconcentrated eluent was purified by silica column chromatography,eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractionswere evaporated to dryness to afford the title compound (77 mg, 22%) asa yellow solid.

1H NMR (399.9 MHz, CDCl3) δ 1.22 (6H, d), 2.71-2.79 (2H, m), 2.84 (1H,d), 2.87 (1H, d), 2.90-3.00 (4H, m), 3.77 (6H, s), 3.83 (2H, s),4.32-4.35 (2H, m), 6.33 (1H, t), 6.36 (2H, d), 6.55 (1H, s), 8.01 (1H,d), 8.92 (1H, d), 9.73 (1H, s), One NH not observed. MS: m/z 505 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0035 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 130N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrazine-2-carboxamide

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(273 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of(2R,6S)-1,2,6-trimethylpiperazine and2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol)in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 2 h. The reaction wasincomplete and N-ethyl-N-propan-2-ylpropan-2-amine (0.24 ml, 1.40 mmol)was added and the solution was stirred at 60° C. for a further 2 h. Thereaction mixture was diluted with methanol (20 mL) and purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH to afford impure material. Theconcentrated eluent was purified by silica column chromatography,eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractionswere evaporated to dryness to afford the title compound (248 mg, 74%) asa yellow solid.

1H NMR (500.13 MHz, DMSO-d6, 373K) δ 1.13-1.14 (6H, m), 2.24 (3H, s),2.25-2.31 (2H, m), 2.81 (1H, d), 2.83 (1H, d), 3.78 (6H, s), 4.30-4.33(2H, m), 5.11 (2H, s), 5.90 (1H, s), 6.46 (1H, t), 6.62 (2H, d), 8.27(1H, d), 8.72 (1H, d), 10.3 (1H, s), 11.1 (1H, s). MS: m/z 482 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00059 μM.

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as outlined in Example 109.

Example 1315-[(3R,5S)-4-(cyanomethyl)-3,5-dimethylpiperazin-1-yl]-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(273 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of(2R,6S)-1,2,6-trimethylpiperazine and2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol)in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 2 h. The reaction wasincomplete and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) was addedand the solution was stirred at 60° C. for a further 2 h. The reactionmixture was diluted with methanol (20 mL) and purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH to afford impure material. The concentratedeluent was purified by silica column chromatography, eluting with agradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporatedto dryness to afford the title compound (65 mg, 18%) as a yellow solid.

1H NMR (399.9 MHz, CDCl3) δ 1.22 (6H, t), 2.72-2.77 (2H, m), 2.86 (1H,d), 2.89 (1H, d), 3.80 (6H, s), 3.83 (2H, s), 4.33-4.37 (2H, m), 5.18(2H, s), 5.50 (1H, s), 6.41 (1H, t), 6.61 (2H, d), 7.99 (1H, d), 8.88(1H, d), 9.62 (1H, s), 10.7 (1H, s). MS: m/z 507 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0035 μM.

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as outlined in Example 109.

Example 132N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.29 ml, 2.58 mmol) was addeddropwise to a suspension of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl (295 mg, 1.03mmol) and methyl 2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate(258 mg, 1.03 mmol) in toluene (5.16 ml) at 25° C. The resultingsolution was stirred at 60° C. for 5 h. The reaction mixture was pouredinto methanol (50 mL) and acidified with HCl (2M aqueous solution). Thecrude product was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The impure materialwas purified by silica column chromatography, eluting with a gradient of0 to 5% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporatedto dryness to afford the title compound (298 mg, 62%) as a whitecrystalline solid.

1H NMR (500.133 MHz, DMSO, 373K) δ 1.05 (3H, d), 2.10-2.20 (2H, m), 2.24(3H, s), 2.81 (1H, dt), 2.91 (1H, dd), 3.24-3.29 (1H, m), 3.76 (6H, s),4.39-4.47 (2H, m), 5.09 (2H, s), 5.71 (1H, s), 6.44 (1H, t), 6.60 (2H,d), 8.84 (2H, s), 10.30 (1H, s), 11.28 (1H, s). MS: m/z 468 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0036 μM.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl was prepared asoutlined in Example 12.

Methyl 2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate used asstarting material was prepared as follows:—

A solution of methyl 2-chloropyrimidine-5-carboxylate (500 mg, 2.90mmol) in dichloromethane (7.50 ml) was added to a stirred solution of1,2-dimethylpiperazine (331 mg, 2.90 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (1.26 ml, 7.24 mmol) indichloromethane (7.25 ml) at room temperature under nitrogen. Theresulting solution was stirred at ambient temperature for 5 h. Thereaction mixture was concentrated under reduced pressure and the crudeproduct was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The impure materialwas purified by silica column chromatography, eluting with a gradient of0 to 5% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporatedto dryness to afford the desired compound (713 mg, 98%) as a yellowsolid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.04-1.06 (3H, m), 1.98-2.05 (1H, m),2.06-2.13 (1H, m), 2.21 (3H, s), 2.78-2.84 (2H, m), 3.14-3.21 (1H, m),3.81 (3H, s), 4.46-4.55 (2H, m), 8.78 (2H, s). MS: m/z 251 (MH+).

Example 1332-(4-cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 2.00 mL, 4.00 mmol) was addeddropwise to a stirred suspension of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl (459 mg, 1.60mmol) and methyl 2-(4-cyclopropylpiperazin-1-yl)pyrimidine-5-carboxylate(421 mg, 1.60 mmol) in toluene (8.0 mL) at 25° C. The resulting solutionwas stirred at ambient temperature for 18 h and then at 60° C. for 2 h.The reaction mixture was quenched with methanol (20 mL) and treated withHCl (2N aqueous solution, until a freely stirred solution was obtained).The crude product was purified by ion exchange chromatography, using anSCX column. The desired product was eluted from the column using 7MNH3/MeOH and evaporated to dryness to afford impure product. The impurematerial was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (94 mg, 12%) as a solid.

1H NMR (500.13 MHz, DMSO-d6, 373K) δ 0.40-0.43 (2H, m), 0.44-0.49 (2H,m), 1.71-1.75 (1H, m), 2.65 (4H, t), 3.78 (6H, s), 3.84 (4H, t), 5.11(2H, s), 5.71 (1H, s), 6.46 (1H, t), 6.62 (2H, d), 8.86 (2H, s), 10.3(1H, s), 11.3 (1H, s). MS: m/z 480 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0039 μM.

Methyl 2-(4-cyclopropylpiperazin-1-yl)pyrimidine-5-carboxylate wasprepared as outlined in Example 126.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl was prepared asoutlined in Example 12.

Example 1342-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 2.50 ml, 5.00 mmol) was addeddropwise to a stirred suspension5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl (572 mg, 2.00mmol) and methyl2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate(525 mg, 2.00 mmol) in toluene (10.00 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 18 h and then at 60° C.for 2 h. The reaction mixture was cautiously quenched with methanol (20mL) and treated with HCl (2N aqueous solution, until a freely stirredsolution was obtained). The crude product was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and evaporated to dryness to afford impureproduct. The impure material was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 0.1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (269 mg, 28%) as a solid.

1H NMR (500.13 MHz, DMSO-d6, 373K) δ 1.39-1.47 (1H, m), 1.69-1.75 (1H,m), 1.76-1.82 (1H, m), 1.84-1.90 (1H, m), 1.99-2.03 (1H, m), 2.13-2.21(2H, m), 2.72-2.78 (1H, m), 3.04-3.13 (3H, m), 3.78 (6H, s), 4.70-4.75(1H, m), 4.85-4.88 (1H, m), 5.11 (2H, s), 5.72 (1H, s), 6.46 (1H, t),6.62 (2H, d), 8.87 (2H, s), 10.30 (1H, s), 11.30 (1H, s). MS: m/z 480(MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0024 μM.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl was prepared asoutlined in Example 12.

Methyl2-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylateused as starting material was prepared as outlined in Example 128.

Example 135N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.31 ml, 2.62 mmol) was addeddropwise to a suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (260 mg, 1.05 mmol)and methyl 2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate (263mg, 1.05 mmol) in toluene (5.26 ml) at 25° C. The resulting solution wasstirred at 60° C. for 18 h. The reaction mixture was poured intomethanol (50 mL) and acidified with HCl (2M aqueous solution, to obtaina clear freely stirring solution). The crude product was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH and evaporated to dryness toafford impure product. The impure material was purified by silica columnchromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH indichloromethane. Fractions containing product were evaporated to drynessto give material that was still impure. The residue was repurified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (175 mg, 36%) asa white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.05-1.07 (3H, m), 1.99-2.05 (1H, m),2.07-2.13 (1H, m), 2.22 (3H, s), 2.76-2.84 (2H, m), 2.88 (4H, s),3.12-3.19 (1H, m), 3.72 (6H, s), 4.46-4.55 (2H, m), 6.33 (1H, t), 6.42(3H, m), 8.89 (2H, s), 10.60 (1H, s), 12.12 (1H, s). MS: m/z 466 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0026 μM.

5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate used asstarting material was prepared as outlined in Example 132.

Example 136N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.04 ml, 2.08 mmol) was addeddropwise to a suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (205 mg, 0.83 mmol)and methyl2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxylate (220mg, 0.83 mmol) in toluene (5.257 ml) at 25° C. The resulting solutionwas stirred at 60° C. for 18 h. The reaction mixture was poured intomethanol (50 mL) and acidified with HCl (2M aqueous solution, to obtaina clear freely stirring solution). The crude product was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH and evaporated to dryness toafford impure product. The impure material was purified by preparativeHPLC, using decreasingly polar mixtures of water (containing 1% NH3) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the title compound (157 mg, 39%) as awhite solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.09-1.10 (6H, m), 2.08-2.14 (2H, m), 2.20(3H, s), 2.71 (1H, d), 2.74 (1H, d), 2.87 (4H, s), 3.72 (6H, s),4.55-4.59 (2H, m), 6.33 (1H, t), 6.42 (3H, m), 8.89 (2H, s), 10.61 (1H,s), 12.15 (1H, s). MS: m/z 480 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0019 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxylateused as starting material was prepared as follows:—

Macroporous triethylammonium methylpolystyrene cyanoborohydride (2.31mmol/g, 3.15 g, 7.29 mmol) was added to methyl2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate (730 mg,2.92 mmol), formaldehyde (37% aqueous solution, 4.43 ml, 59.13 mmol) andacetic acid (0.334 ml, 5.83 mmol) in methanol (5.83 ml) at 25° C. Theresulting suspension was stirred at ambient temperature for 5 h. Themacroporous triethylammonium methylpolystyrene cyanoborohydride wasremoved by filtration, washing with methanol (50 mL). The filtrate waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford impure product. The impure material waspurified by silica column chromatography, eluting with a gradient of 0to 6% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporated todryness to afford the desired compound (474 mg, 62%) as a white oilwhich solidified on standing.

1H NMR (399.9 MHz, DMSO-d6) δ 1.09 (6H, d), 2.07-2.15 (2H, m), 2.19 (3H,s), 2.73-2.76 (2H, m), 3.81 (3H, s), 4.56-4.60 (2H, m), 8.79 (2H, s).MS: m/z 265 (MH+).

Methyl 2-((3R,5S)-3,5-dimethylpiperazin-1-yl)pyrimidine-5-carboxylateused as starting material was prepared as follows:—

A solution of methyl 2-chloropyrimidine-5-carboxylate (535 mg, 3.10mmol) in dichloromethane (7.50 ml) was added to a stirred solution of(2S,6R)-2,6-dimethylpiperazine (354 mg, 3.10 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (1.35 ml, 7.75 mmol) indichloromethane (7.24 ml) at room temperature under nitrogen. Theresulting solution was stirred at ambient temperature for 3 h. Thereaction mixture was concentrated under reduced pressure and the crudeproduct was purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The impure materialwas purified by silica column chromatography, eluting with a gradient of0 to 5% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporatedto dryness to afford the desired compound (740 mg, 95%) as a whitesolid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.02-1.04 (6H, m), 2.33 (1H, s), 2.43-2.46(2H, m), 2.64-2.69 (2H, m), 3.81 (3H, s), 4.62-4.66 (2H, m), 8.77 (2H,s). MS: m/z 251 (MH+).

Example 137N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[4-(1-hydroxypropan-2-yl)piperazin-1-yl]benzamide

2-(Piperazin-1-yl)propan-1-ol 2HCl (0.274 g, 1.26 mmol) was added toN-ethyl-N-propan-2-ylpropan-2-amine (0.330 mL, 1.89 mmol) in DMSO (5mL). The reaction mixture was stirred at room temperature for 10 mins.N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide(0.233 g, 0.63 mmol) was added and the mixture heated at 110° C. for 18h under nitrogen. Heating was continued for 12 additional days. Thereaction was cooled and the crude mixture was purified by ion exchangechromatography, using a SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and pure fractions were evaporated todryness to afford crude product. The crude product was purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (0.048 g,15.44%) as a cream solid.

1H NMR (500.13 MHz-DMSO-d6+CD3COOD @ 373K): 1.02 (3H, d), 2.70-2.81 (5H,m), 2.89 (4H, s), 3.28-3.34 (4H, m), 3.37-3.44 (1H, m), 3.50-3.55 (1H,m), 3.73 (6H, s), 6.27-6.32 (2H, m), 6.40 (2H, s0, 6.92 (2H, d),7.82-7.88 (2H, m). MS: m/z (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00057 μM.

2-(Piperazin-1-yl)propan-1-ol. 2HCl used as starting material wasprepared as follows:

A 1M solution of borane tetrahydrofuran complex (12.00 mL, 12.00 mmol)in THF, was added dropwise to a stirred suspension of2-(1-tert-butoxycarbonylpiperazin-4-yl)propionic acid (2.58 g, 10 mmol)in tetrahydrofuran (50 mL) at 0° C., over a period of 10 mins undernitrogen. The resulting solution was stirred at 60° C. for 8 h. This wasquenched with acetic acid/water (10 ml, 1:2 mixture) and evaporated todryness. The residue was dissolved in ethyl acetate (50 ml), washed withsaturated sodium bicarbonate (25 ml) and water, dried over MgSO₄,filtered and evaporated to dryness to give tert-butyl4-(1-hydroxypropan-2-yl)piperazine-1-carboxylate (0.810 g, 33.2%)

1H NMR (399.9 MHz, CDCl3) δ 0.83 (3H, d), 1.39 (9H, s), 2.30 (2H, t),2.51-2.57 (3H, m), 2.71-2.82 (1H, m), 3.34-3.40 (2H, m), 3.35-3.39 (4H,m).

A suspension of tert-butyl4-(1-hydroxypropan-2-yl)piperazine-1-carboxylate (0.782 g, 3.2 mmol) ina mixture of ethyl acetate (10 ml) and methanol (10.00 mL), was treateddrop-wise with 4.0M HCl in dioxane (12.00 ml, 48.00 mmol) at roomtemperature. The reaction mixture was stirred for 18 h. The reactionmixture was diluted with ether and the white solid filtered off, washedwith ether and air dried to give 2-(piperazin-1-yl)propan-1-ol (0.525 g,76%), as its dihydrochloride salt.

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamideused as starting material was prepared as follows:

A 2M solution of trimethylaluminium in toluene (3.00 mL, 3.00 mmol) wasadded drop-wise to a stirred solution of ethyl 4-fluorobenzoate (0.440mL, 3.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine(0.742 g, 3 mmol) in toluene (10 mL) at room temperature. The reactionwas stirred at room temperature for 18 h. The reaction mixture waspoured into acetone (50 mL) and treated with an excess of damp sodiumsulphite. The reaction mixture was purified by ion exchangechromatography, using a SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and fractions were evaporated to dryness toafford a yellow gum. The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/MeOH inDCM. Pure fractions were evaporated to dryness to afford the desiredcompound (0.245 g, 22.11%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 2.88 (4H, s), 3.73 (6H, s), 6.33 (1H, t),6.42 (2H, d), 6.47 (1H, s), 7.32 (2H, t), 8.05-8.09 (2H, m), 10.69 (1H,s), 12.16 (1H, s). MS: m/z 370 (MH+).

Example 138N-(3-(3,5-dimethoxybenzyloxy)-1H-pyrazol-5-yl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.04 mL, 2.07 mmol) was addeddropwise to a suspension of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl (237 mg, 0.83mmol) and methyl2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxylate (219mg, 0.83 mmol) in toluene (4.2 mL) at 25° C. The resulting solution wasstirred at 60° C. for 2 h. The reaction mixture was poured into methanol(50 mL) and acidified with HCl (2M aqueous solution). The crude productwas purified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford impure product. The impure material waspurified by preparative HPLC, using decreasingly polar mixtures of water(containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(158 mg, 40%) as a white solid.

1H NMR (500.133 MHz, DMSO, 373K) δ 1.10 (6H, d), 2.14-2.20 (2H, m), 2.22(3H, s), 2.74-2.79 (2H, m), 3.76 (6H, s), 4.53-4.57 (2H, m), 5.08 (2H,s), 5.71 (1H, s), 6.44 (1H, t), 6.59 (2H, d), 8.84 (2H, s), 10.32 (1H,s), 11.31 (1H, s). MS: m/z 482 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0026 μM.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl was prepared asoutlined in Example 12.

Methyl 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)pyrimidine-5-carboxylatewas prepared as outlined in Example 136.

Example 139N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,3-dimethylpiperazin-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide(0.1 g, 0.27 mmol) and 2,2-dimethylpiperazine (0.124 g, 1.04 mmol) werestirred at 60° C. for 20 mins. Potassium carbonate (0.033 ml, 0.54 mmol)and DMSO (1 ml) were added and the reaction stirred at 120° C. in asealed tube for 16 days. The reaction mixture was cooled and evaporated.The crude product was purified by preparative HPLC, using decreasinglypolar mixtures of water (containing 1% NH₃) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford the title compound (6.00 mg, 2.000%) as a colourless gum.

1H NMR (399.9 MHz, CDCl3) δ 1.19 (6H, s), 2.92-2.95 (4H, m), 3.02 (4H,d), 3.04 (1H, s), 3.17 (2H, t), 3.75 (6H, s), 6.32-6.35 (3H, m), 6.84(2H, d), 7.77 (2H, d), 8.73 (1H, s). MS: m/z 465 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00047 μM.

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamideused as starting material was prepared as follows:—

A 2M solution of trimethylaluminium (3.54 ml, 7.08 mmol) in toluene wasadded dropwise to 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine(0.7 g, 2.83 mmol) in toluene (35 ml). Methyl 4-fluorobenzoate (0.366ml, 2.83 mmol) was then added and the resulting solution was stirred atroom temperature for 18 h. An additional amount of methyl4-fluorobenzoate (0.183 ml, 1.42 mmol) was added and the solution wasstirred at room temperature for a further 20 h. The reaction mixture waspoured into acetone (40 ml), and treated with an excess of damp sodiumsulfite solution. The suspension was stirred for 2 h, filtered and thefiltrate was purified by silica column chromatography, eluting with agradient 2.5 to 5% 2.5N NH₃/MeOH in DCM. Pure fractions were evaporatedto dryness to afford the desired compound as a beige oil whichsolidified on standing (0.147 g, 14.06%) to a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 2.88 (4H, s), 3.73 (6H, s), 6.33 (1H, t),6.43 (2H, d), 6.47 (1H, s), 7.31 (2H, t), 8.05-8.09 (2H, m), 10.69 (1H,s), 12.16 (1H, s). MS: m/z 370 (MH+).

Example 140N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxamide

2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was addeddropwise to a stirred solution of ethyl5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.268 g, 1 mmol)and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride(0.286 g, 1.00 mmol) in toluene (7.14 ml) at 65° C. under nitrogen. Thereaction mixture was stirred and heated at 65° C. for 4 h then 50° C.for 18 h followed by 80° C. for 5 h. Ethyl acetate (5 mL) was added tothe reaction mixture followed by a solution of potassium sodium tartrate(5 mL, 20% aqueous). More ethyl acetate (50 mL) and water (25 mL) wasadded and the mixture was filtered through celite. The filtrate wastransferred to a separating funnel and the aqueous layer removed. Theethyl acetate layer was washed with saturated brine and then dried overmagnesium sulphate. After filtration the solvent was evaporated to givethe crude product as a yellow gum. The crude product was purified bypreparative LCMS, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (0.073 g,15.48%) as a white solid.

1H NMR (500.13 MHz, DMSO-d6, CD3CO2D) δ 1.36 (6H, s), 3.24 (4H, s), 3.40(2H, t), 3.74 (6H, s), 5.06 (2H, s), 5.64 (1H, s), 6.24 (1H, d), 6.41(1H, s), 6.57 (2H, s), 7.62-7.63 (1H, m); MS: m/z 472 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00098 μM.

Ethyl 5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxylate, used asstarting material was prepared as follows:—

Palladium(II) acetate (0.112 g, 0.50 mmol) was added to ethyl5-bromothiophene-2-carboxylate (1.175 g, 5 mmol),2,2-dimethyl-piperazine (0.571 g, 5.00 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) andcesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C.under nitrogen. The resulting suspension was stirred at 110° C. for 23h. The crude product was purified by ion exchange chromatography, usinga SCX2 column. The crude material was dissolved in methanol and thenapplied to the column. The desired product was eluted from the columnusing 2M NH3 in methanol and pure fractions were evaporated to drynessto afford the crude product as a brown solid.

This material was further purified by silica column chromatography,eluting with a gradient of 0 to 4% MeOH in DCM. Pure fractions wereevaporated to dryness to afford ethyl5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.484 g, 36.1%)as a brown gum.

1H NMR (399.9 MHz, CDCl3) δ 1.20 (6H, s), 1.33 (3H, t), 2.98 (2H, s),3.05 (2H, d), 3.16-3.19 (2H, m), 4.28 (2H, q), 6.00 (1H, d), 7.54 (1H,d)

MS: m/z 269 (MH+)

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as in Example 12.

Example 141N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-ethylpiperazin-1-yl)thiophene-2-carboxamide

Trimethylaluminium (2M solution in toluene, 1.40 mL, 2.79 mmol) wasadded dropwise to a stirred suspension of5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl (319 mg, 1.12mmol) and ethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylate (300mg, 1.12 mmol) in toluene (5.60 mL) at 25° C. The resulting solution wasthen stirred at 60° C. under nitrogen for 5 h. The reaction mixture wascautiously quenched into methanol (100 mL), acidified with HCl (2Maqueous solution) and the mixture was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and evaporated to dryness to afford impurematerial. The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM.Fractions were evaporated to dryness to afford impureN-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-ethylpiperazin-1-yl)thiophene-2-carboxamideas a cream solid. The residue was repurified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (72 mg, 14%) as a white solid.

1H NMR (500.133 MHz, DMSO, 373K) δ 1.04 (3H, t), 2.43 (2H, q), 2.53-2.54(4H, m), 3.23-3.25 (4H, m), 3.76 (6H, s), 5.07 (2H, s), 5.60 (1H, s),6.14 (1H, d), 6.44 (1H, t), 6.59 (2H, d), 7.63 (1H, d), 10.05 (1H, s),11.09 (1H, s). MS: m/z 472 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00086 μM.

Ethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylate used as startingmaterial was prepared as follows:—

Tris(dibenzylideneacetone)dipalladium(0) (183 mg, 0.20 mmol) followed bysodium tert-butoxide (538 mg, 5.60 mmol) was added to ethyl5-bromothiophene-2-carboxylate (1.034 g, 4.40 mmol), 1-ethylpiperazine(0.51 ml, 4.00 mmol) and(rac)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (249 mg, 0.40mmol) in toluene (20.00 ml) at 25° C. under nitrogen. The resultingsuspension was stirred at 110° C. for 18 h. The cooled reaction mixturewas diluted with methanol and purified by ion exchange chromatography,using an SCX column. The desired product was eluted from the columnusing 7M NH3/MeOH and evaporated to dryness to afford crude product. Theresidue was purified by silica column chromatography, eluting with agradient of 0 to 3% 7M NH3/MeOH in DCM. Fractions containing desiredproduct were evaporated to dryness to give impure orange oil. The impurematerial was further purified by preparative HPLC, using decreasinglypolar mixtures of water (containing 1% NH3) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford ethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylate (339 mg,32%) as a yellow oil.

1H NMR (399.902 MHz, DMSO) δ 1.03 (3H, t), 1.25 (3H, t), 2.38 (2H, q),2.49 (4H, m), 3.24 (4H, m), 4.19 (2H, q), 6.21 (1H, d), 7.51 (1H, d).MS: m/z 269 (MH+)

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl was prepared asoutlined in Example 12.

Example 142N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxamide

Ethyl 5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxylate (0.201 g,0.75 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine(0.185 g, 0.75 mmol) in toluene (10 mL) were stirred at 20° C. and a 2Msolution of trimethylaluminium in toluene (0.938 mL, 1.88 mmol) wasadded drop-wise. The reaction stirred under nitrogen at 60° C. for 18 h.The reaction mixture was cooled and quenched by pouring into methanol(50 ml), acidified with few drops of 2N hydrochloric acid. The crudeproduct was purified by ion exchange chromatography, using a SCX column.The desired product was eluted from the column using 7M NH3/MeOH andfractions were evaporated to dryness to afford crude product.

The crude product was purified by preparative HPLC, using decreasinglypolar mixtures of water (containing 1% NH3) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford the title compound (0.162 g, 46.0%) as a tan solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.89-1.93 (2H, m), 2.28 (3H, s), 2.50-2.54(2H, m), 2.63 (1H, d), 2.64-2.65 (1H, m), 2.85 (4H, s), 3.43 (2H, t),3.50 (2H, t), 3.72 (6H, s), 5.86 (1H, d), 6.32-6.34 (2H, m), 6.41 (2H,d), 7.79 (1H, d), 10.15 (1H, s), 12.00 (1H, s). MS: m/z 470 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0021 μM.

Ethyl 5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxylate was preparedas follows: Palladium(II)acetate (0.135 g, 0.60 mmol) was added to ethyl5-bromothiophene-2-carboxylate (1.411 g, 6 mmol), 1-methyl-1,4-diazepane(0.822 g, 7.20 mmol), BINAP (0.374 g, 0.60 mmol) and cesium carbonate(2.74 g, 8.40 mmol) in dioxane (40 mL) warmed to 80° C. for 18 h undernitrogen. The crude reaction mixture was purified by ion exchangechromatography, using a SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH. Fractions were evaporated to dryness toafford the crude product. The crude product was purified by silicacolumn chromatography, eluting with a gradient of 0 to 5% 3Mammonia/MeOH in DCM. Pure fractions were evaporated to dryness to affordethyl 5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxylate (0.204 g,12.67%) as a yellow gum.

1H NMR (399.9 MHz, CDCl3) δ: 1.34 (3H, t), 1.97-2.04 (2H, m), 2.38 (3H,s), 2.55-2.61 (2H, m), 2.67 (2H, m), 3.48 (2H, t), 3.54-3.57 (2H, m),4.28 (4H, q), 5.79 (1H, d), 7.55 (1H, d). MS: m/z 269 (MH+).

Example 143N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-ethyl-3-methylpiperazin-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.65 ml, 3.31 mmol) was addeddropwise to a stirred suspension of methyl2-(4-ethyl-3-methylpiperazin-1-yl)pyrimidine-5-carboxylate (303 mg, 1.15mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (283 mg,1.15 mmol) in toluene (5.73 ml) at room temperature. The resultingsolution was stirred at 60° C. overnight. The reaction mixture wasquenched into methanol (100 mL) and treated with HCl (2N aqueoussolution, until the pH was 7 or lower). The crude product was purifiedby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and fractions wereevaporated to dryness to afford impure product as a yellow dry film. Thecrude product was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (269 mg, 49%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 0.99 (3H, d), 1.03 (3H, d), 2.20-2.26 (1H,m), 2.35-2.43 (2H, m), 2.74-2.79 (1H, m), 2.83 (1H, m), 2.88 (4H, s),3.02-3.07 (1H, m), 3.30-3.38 (1H, m), 3.72 (6H, s), 4.27-4.31 (2H, m),6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 8.89 (2H, s), 10.58 (1H, s),12.15 (1H, s). MS: m/z 480 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0027 μM.

Methyl 2-(4-ethyl-3-methylpiperazin-1-yl)pyrimidine-5-carboxylate, usedas starting material, was prepared as follows:

A solution of methyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.74mmol) in dichloromethane (4.30 ml) was added to a stirred solution of1-ethyl-2-methylpiperazine (223 mg, 1.74 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (0.75 ml, 4.35 mmol) indichloromethane (4.40 ml) at 25° C. under nitrogen. The resultingsolution was stirred at room temperature for 4 h. The reaction mixturewas concentrated under reduced pressure and diluted with MeOH (10 mL).The crude product was purified by ion exchange chromatography, using aSCX column. The desired product was eluted from the column using 7MNH3/MeOH and was evaporated to dryness to afford impure product. Thecrude product was purified by silica column chromatography, eluting witha gradient of 0 to 3% 7M NH₃/MeOH in dichloromethane. Pure fractionswere evaporated to dryness to afford the desired compound (382 mg, 83%)as a colourless oil.

1H NMR (399.9 MHz, DMSO-d₆) δ 0.98 (3H, t), 1.02 (3H, d), 2.20-2.27 (1H,m), 2.33-2.38 (1H, m), 2.40-2.45 (1H, m), 2.71-2.79 (1H, m), 2.81-2.85(1H, m), 3.06-3.11 (1H, m), 3.35-3.42 (1H, m), 3.81 (3H, s), 4.28-4.35(2H, m), 8.78 (2H, s). MS: m/z 265 (MH+)

Example 144N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-enylpiperidin-4-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-enylpiperidin-4-yl)benzamidewas prepared following the procedure as outlined for Example 99,starting from methyl 4-(1-prop-2-enylpiperidin-4-yl)benzoate (0.259 g,1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine(0.247 g, 1 mmol) and 2M trimethylaluminium (1.250 mL, 2.50 mmol) intoluene (10 ml). The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanolin DCM. Pure fractions were evaporated to dryness and the product wascrystallised from DCM/diethyl ether to give on filtration the titlecompound (0.182 g, 38.3%) as a white solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 1.66-1.70 (2H, m), 1.73-1.79 (2H, m),1.99-2.05 (2H, m), 2.55 (1H, d), 2.88 (4H, s), 2.95 (1H, s), 2.99 (3H,d), 3.73 (6H, s), 5.12-5.18 (1H, m), 5.22 (1H, t), 5.83-5.89 (1H, m),6.33 (1H, t), 6.43 (2H, d), 6.47 (1H, s), 7.35 (2H, d), 7.93 (2H, d),10.55 (1H, s), 12.13 (1H, s). MS: m/z 475 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.000041 μM.

Methyl 4-(1-prop-2-enylpiperidin-4-yl)benzoate used as starting materialwas prepared as follows:

3-Bromoprop-1-ene (0.433 mL, 5.00 mmol) was added dropwise over 5 minsunder nitrogen to a stirred solution of methyl 4-piperidin-4-ylbenzoate(1.096 g, 5 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.066 mL, 12.50mmol) in DCM (10 mL) at room temperature. The reaction mixture wasstirred for 1 h at room temperature. This was evaporated to dryness andpartially purified on a SCX column, eluting with 3.5N ammonia inmethanol. Fractions containing product were combined and evaporated todryness. The crude product was purified by silica column chromatography,eluting with 5% MeOH in DCM. Pure fractions were evaporated to drynessto afford the desired compound (1.004 g, 77%) as a white solid.

1H NMR (399.9 MHz, CDCl3) δ 1.78-1.86 (4H, m), 2.02-2.08 (2H, m),2.53-2.57 (1H, m), 3.03-3.05 (3H, m), 3.07 (1H, t), 3.90 (3H, s),5.14-5.23 (2H, m), 5.85-5.97 (1H, m), 7.28-7.31 (2H, m), 7.95-7.98 (2H,m). MS: m/z 260 (MH+).

Methyl 4-piperidin-4-ylbenzoate was prepared as outlined in Example 99.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 1454-(1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

4-(1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamidewas prepared following the procedure as outlined for Example 99,starting from ethyl 4-(1,4-diazepan-1-yl)benzoate (0.497 g, 2 mmol) and5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol)and 2M trimethylaluminium (2.50 mL, 5.0 mmol) in toluene (10 ml). Thecrude product was purified by silica column chromatography, eluting witha gradient of 0 to 10% 2.5 M ammonia MeOH in DCM. Fractions containingthe product were evaporated to dryness and further purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (0.024 g, 2.67%)as a white solid.

1H NMR (500.13 MHz, DMSO-d6+d4HOAc) δ 2.07 (2H, t), 2.90 (4H, s), 3.10(2H, t), 3.24 (2H, t), 3.62 (2H, t), 3.74-3.76 (8H, m), 6.33 (2H, t),6.42 (2H, d), 6.81-6.83 (2H, m), 7.88-7.89 (2H, m). MS: m/z 450 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0007 μM.

Ethyl 4-(1,4-diazepan-1-yl)benzoate used as starting material wasprepared as follows: Ethyl 4-fluorobenzoate (11.01 mL, 75 mmol) and1,4-diazepane (30.0 g, 300.00 mmol) in DMSO (150 mL) warmed to 100° C.under nitrogen. The resulting solution was stirred at 100° C. for 24 h.The reaction mixture was cooled and evaporated to dryness. The reactionmixture was quenched with 2M NaOH (150 mL), extracted with EtOAc (3×75mL), the organic layer was washed with saturated brine (100 ml), driedover MgSO₄, filtered and evaporated to afford ethyl4-(1,4-diazepan-1-yl)benzoate (17.43 g, 94%) as a colourless oil.

1H NMR (399.9 MHz, CDCl3) δ 1.27-1.31 (3H, m), 1.71 (1H, s), 1.79-1.85(2H, m), 2.74 (1H, d), 2.74 (1H, d), 2.95 (1H, d), 2.96 (1H, d), 3.51(2H, t), 3.56 (2H, t), 4.21-4.27 (2H, m), 6.56-6.60 (2H, m), 7.80-7.83(2H, m). MS: m/z 249 (MH+).

5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 146N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-ynylpiperidin-4-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-ynylpiperidin-4-yl)benzamidewas prepared following the procedure as outlined for Example 99,starting from methyl 4-(1-prop-2-ynylpiperidin-4-yl)benzoate (0.257 g,1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine(0.247 g, 1 mmol) in dry toluene (10 mL) with 2M trimethylaluminium(1.250 mL, 2.50 mmol). The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanolin DCM. Pure fractions were evaporated to dryness and the productcrystallised from DCM/diethyl ether to give the title compound (0.245 g,51.8%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6+d4HOAc) δ 1.64-1.73 (2H, m), 1.79 (2H, d),2.24-2.29 (2H, m), 2.49-2.54 (1H, m), 2.88 (4H, s), 2.90 (1H, s), 2.93(1H, s), 3.15 (1H, t), 3.73 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.44(1H, s), 7.36 (2H, d), 7.93 (2H, d), 10.57 (1H, s), 11.95 (4H, s). MS:m/z 473 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0011 μM.

Methyl 4-(1-prop-2-ynylpiperidin-4-yl)benzoate used as starting materialwas prepared following the procedure as for methyl4-(1-prop-2-enylpiperidin-4-yl)benzoate (Example 144), but starting from3-bromoprop-1-yne (0.356 mL, 4.00 mmol) (80% solution in toluene),methyl 4-piperidin-4-ylbenzoate (0.877 g, 4 mmol) andN-ethyl-N-isopropylpropan-2-amine (1.653 mL, 10.00 mmol) in DCM (5 mL).The crude product was purified by silica column chromatography, elutingwith 5% MeOH in DCM. Pure fractions were evaporated to dryness to affordthe desired compound (0.748 g, 72.7%) as a white solid. 1H NMR (399.9MHz, CDCl3) δ 1.81-1.90 (4H, m), 2.27 (1H, t), 2.32-2.38 (2H, m),2.54-2.59 (1H, m), 3.00-3.04 (2H, m), 3.36 (2H, d), 3.90 (3H, s),7.27-7.30 (2H, m), 7.95-7.98 (2H, m). MS: m/z 258 (MH+).

Methyl 4-piperidin-4-ylbenzoate was prepared as outlined in Example 144.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 147N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-[(3S,5R)-3,5-dimethylpiperazin-1-yl]thiophene-2-carboxamide

2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was addeddropwise to a stirred solution of ethyl5-((3R,5S)-3,5-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.268 g,1 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-aminehydrochloride (0.286 g, 1.00 mmol) in toluene (7.14 ml) at roomtemperature and then the mixture was heated at 80° C. under nitrogen for4 h and then at 70° C. for 18 h. Ethyl acetate (5 mL) was added to thereaction mixture followed by a solution of potassium sodium tartrate (5mL, 20% aqueous). More ethyl acetate (50 mL) and water (25 mL) was addedand the mixture was filtered through celite. The filtrate wastransferred to a separating funnel and the aqueous layer removed. Theethyl acetate layer was washed with saturated brine and then dried overmagnesium sulphate. After filtration the solvent was evaporated to givethe crude product as a yellow gum. The crude product was purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (0.154 g, 32.7%)as a white solid.

1H NMR (500.13 MHz, DMSO-d6, CD3CO2D) δ 1.23 (6H, d), 2.79 (2H, t),3.26-3.34 (2H, m), 3.63-3.66 (2H, m), 3.76 (6H, s), 5.08 (2H, s), 5.63(1H, s), 6.25 (1H, d), 6.43 (1H, t), 6.59 (2H, d), 7.66 (1H, d), 11.08(1H, s)

MS: m/z 472 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0018 μM.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as in Example 12.

Ethyl 5-((3R,5S)-3,5-dimethylpiperazin-1-yl)thiophene-2-carboxylate,used as starting material was prepared as follows:—

Palladium(II) acetate (0.225 g, 1.00 mmol) was added to ethyl5-bromothiophene-2-carboxylate (2.351 g, 10 mmol),(2S,6R)-2,6-dimethylpiperazine (1.142 g, 10.00 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.623 g, 1.00 mmol) andcesium carbonate (4.56 g, 14.00 mmol) in dioxane (100 ml) at 20° C.under nitrogen. The resulting suspension was stirred at 105° C. for 23h. The mixture was evaporated to dryness to give a brown oil. This crudeproduct was purified by ion exchange chromatography, using a SCX2column. The crude material was dissolved in methanol and then applied tothe column. The desired product was eluted from the column using 2M NH3in methanol and pure fractions were evaporated to dryness to afford thecrude product as a brown solid.

This material was further purified by silica column chromatography,eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions wereevaporated to dryness to afford ethyl5-((3S,5R)-3,5-dimethylpiperazin-1-yl)thiophene-2-carboxylate (1.600 g,59.6%) as a white solid.

1H NMR (399.9 MHz, CDCl3) δ 1.12-1.14 (6H, m), 1.33 (3H, t), 2.46-2.56(2H, m), 2.98-3.07 (2H, m), 3.42-3.46 (2H, m), 4.28 (2H, q), 6.00 (1H,d), 7.55 (1H, d)

MS: m/z 269 (MH+)

Example 148N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[1-(2-methoxyethyl)piperidin-4-yl]benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[1-(2-methoxyethyl)piperidin-4-yl]benzamidewas prepared following the procedure as outlined for Example 99,starting from methyl 4-(1-(2-methoxyethyl)piperidin-4-yl)benzoate (0.428g, 1.25 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine(0.309 g, 1.25 mmol) and 2M trimethylaluminium (1.56 mL, 3.13 mmol) intoluene (10 ml). The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanolin DCM. Pure fractions were evaporated to dryness and the product wascrystallised from DCM/diethyl ether to afford the title compound (0.215g, 34.9%) as an off white solid.

1H NMR (399.9 MHz, CDCl3) δ 1.76-1.91 (4H, m), 2.10-2.17 (2H, m),2.54-2.58 (1H, m), 2.63 (2H, t), 2.92-2.96 (4H, m), 3.10 (2H, d), 3.37(3H, s), 3.56 (2H, t), 3.76 (6H, s), 6.33-6.35 (3H, m), 6.68 (1H, s),7.32 (2H, d), 7.80 (2H, d), 8.65 (1H, s), 9.28 (1H, s). MS: m/z 493(MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00087 μM.

Methyl 4-(1-(2-methoxyethyl)piperidin-4-yl)benzoate used as startingmaterial was prepared as follows:

A solution of methyl 4-(piperidin-4-yl)benzoate, HCl (1.279 g, 5 mmol),N-ethyl-N-propan-2-ylpropan-2-amine (3.49 mL, 20.00 mmol) and1-bromo-2-methoxyethane (0.470 mL, 5.00 mmol) in dichloromethane (10 mL)was heated at 40° C. or 18 h. A few drops of DMF were added to aidsolubility. The reaction mixture was cooled, diluted with DCM (30 ml)and washed with water (2×30 ml) and saturated sodium chloride solution(30 ml). This was dried over MgSO₄, filtered and evaporated to dryness.The crude product was purified by silica column chromatography, elutingwith a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporatedto dryness to afford methyl 4-(1-(2-methoxyethyl)piperidin-4-yl)benzoate(0.723 g, 52.1%) as a colourless oil.

1H NMR (399.9 MHz, CDCl3) δ 1.75 (1H, t), 1.81-1.90 (3H, m), 2.09-2.15(2H, m), 2.55 (1H, q), 2.60-2.63 (2H, m), 3.08-3.11 (2H, m), 3.37 (3H,s), 3.53-3.56 (2H, m), 3.89-3.90 (3H, m), 7.27-7.31 (2H, m), 7.95-7.98(2H, m). MS: m/z 278 (MH+).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 149N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-[(3S)-3-propan-2-ylpiperazin-1-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was addeddropwise to a stirred suspension of (S)-methyl2-(3-propan-2-ylpiperazin-1-yl)pyrimidine-5-carboxylate (260 mg, 0.98mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg,0.98 mmol) in toluene (8.38 mL) at room temperature. The reaction wasthen stirred at 60° C. for 18 h under a nitrogen atmosphere. Thereaction mixture was quenched into methanol (100 mL) and treated withHCl (2N aqueous solution, until the pH was 7 or lower). The crudeproduct was purified by ion exchange chromatography, using a SCX column.The desired product was eluted from the column using 7M NH3/MeOH andfractions were evaporated to dryness to afford impure product. The crudeproduct was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (292 mg, 62%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.95-0.97 (6H, d), 1.63 (1H, m), 2.26-2.31(1H, m), 2.57-2.64 (1H, m), 2.68 (1H, d), 2.88 (4H, s), 2.89-2.97 (1H,m) 2.98-3.02 (1H, m), 3.72 (6H, s), 4.57 (1H, d), 4.66 (1H, d), 6.33(1H, t), 6.41-6.44 (3H, m), 8.88 (2H, s), 10.56 (1H, s), 12.14 (1H, s).MS: m/z 480 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0044 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

(S)-methyl 2-(3-propan-2-ylpiperazin-1-yl)pyrimidine-5-carboxylate, usedas starting material was prepared as follows:

A solution of (2S)-2-propan-2-ylpiperazine (223 mg, 1.74 mmol) indichloromethane (4.40 mL) was added to a stirred solution of methyl2-chloropyrimidine-5-carboxylate (300 mg, 1.74 mmol) in dichloromethane(4.30 mL) at 25° C. N-Ethyl-N-propan-2-ylpropan-2-amine (0.752 mL, 4.35mmol) was added. The resulting solution was stirred at room temperaturefor 18 h under a nitrogen atmosphere. The reaction mixture wasconcentrated and diluted with methanol. The crude product was purifiedby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and fractions wereevaporated to dryness to afford the desired compound (456.1 mg, 99%) asa yellow oil.

This was used directly with no further purification.

1H NMR (399.9 MHz, DMSO-d₆) δ 0.94-0.96 (6H, m), 1.58-1.66 (1H, m),2.25-2.30 (1H, m), 2.56-2.63 (1H, m), 2.68-2.74 (1H, m), 2.95-3.02 (2H,m), 3.81 (3H, s), 4.56-4.60 (1H, m), 4.64-4.68 (1H, m), 8.78 (2H, s).MS: m/z 265 (MH+)

(2S)-2-propan-2-ylpiperazine, used as starting material was prepared asfollows:

A solution of tert-butyl (2S)-2-propan-2-ylpiperazine-1-carboxylate (2g, 8.76 mmol) in a mixture of ethyl acetate (20 mL) and methanol (20.00mL) was stirred at room temperature with 4M HCl in dioxane (30 mL) for40 h under nitrogen. The reaction mixture was evaporated to dryness. Thecrude product was purified by ion exchange chromatography, using a SCXcolumn. The desired product was eluted from the column using 3.5MNH3/MeOH and pure fractions were evaporated to dryness to afford(2S)-2-propan-2-ylpiperazine (1.052 g, 94%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.83-0.87 (6H, m), 1.39-1.47 (1H, m),2.15-2.22 (2H, m), 2.41-2.47 (1H, m), 2.53-2.59 (1H, m), 2.67 (1H, d),2.75-2.80 (2H, m)—2 protons not seen.

Example 150N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was addeddropwise to a stirred suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol)and methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246mg, 0.98 mmol) in toluene (5.00 mL) at 25° C. The resulting solution wasstirred at 60° C. for 24 h. The reaction mixture was added to methanol(100 mL), then treated with HCl (2N aqueous solution, until pH was 7 orlower). The crude product was purified by ion exchange chromatography,using a SCX column. The desired product was eluted from the column using7M NH3/MeOH and fractions were evaporated to dryness to afford impureproduct. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 0.1% TFA) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (204 mg, 45%) as a white solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 2.88-2.91 (7H, m), 3.44 (2H, t), 3.72 (6H,s), 4.08 (2H, t), 4.33 (2H, s), 6.33 (1H, t), 6.40-6.47 (3H, m), 8.95(2H, s), 10.66 (1H, s), 12.16 (1H, s).

MS: m/z 466 (MH+)

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.012 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate, used asstarting material was prepared as follows:

A solution of 1-methylpiperazin-2-one (198 mg, 1.74 mmol) indichloromethane (4.00 mL) was added to a stirred solution of methyl2-chloropyrimidine-5-carboxylate (300 mg, 1.74 mmol) in dichloromethane(4.70 mL) at 25° C. The resulting solution was stirred at roomtemperature for 4 h under nitrogen. The reaction mixture wasconcentrated and dissolved in ethyl acetate (25 ml) and NaOH (50 ml, 1Maqueous solution). The organic layer was washed with ethyl acetate (25ml). The organic layers were combined and washed with brine (50 ml),dried using MgSO₄, filtered and evaporated to dryness to afford methyl2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246 mg, 57%)as a cream solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 2.91 (3H, s), 3.44 (2H, t), 3.83 (3H, s),4.09 (2H, t), 4.35 (2H, s), 8.86 (2H, s). MS: m/z 501 (2MH+)

Example 1514-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide

4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamidewas prepared following the procedure as for Example 115, but startingfrom methyl4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)benzoate (0.221g, 0.85 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amineHCl (0.243 g, 0.85 mmol) and 2M trimethylaluminium in toluene (1.06 ml,2.13 mmol). The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (0.124 g, 30.5%) as a white solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 1.36-1.45 (1H, m), 1.50-1.60 (1H, m),1.63-1.75 (2H, m), 2.12 (1H, s), 2.27-2.38 (1H, m), 2.83 (1H, d), 3.16(1H, d), 3.26-3.36 (2H, m), 3.37-3.45 (2H, m), 3.85 (6H, s), 5.08 (2H,s), 5.54 (1H, s), 6.44 (1H, s), 6.52 (2H, d), 6.57 (2H, s), 7.82 (2H,d), 10.46 (1H, s0, 11.45 (1H, s). 1 proton not seen. MS: m/z 478 (MH+).

Mean of n=3, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0013 μM.

Methyl 4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)benzoateused as starting material was prepared as follows:

2,3,4,4a,5,6,7,7a-Octahydro-1H-pyrrolo[3,4-b]pyridine. 2HCl (0.813 g, 5mmol) was dissolved in water (10 ml) and placed on a SCX2 column (50 g).This was washed through with methanol and released the freebase from thecolumn with 7N ammonia in methanol. The freebase and methyl4-fluorobenzoate (0.291 mL, 2.25 mmol) were dissolved in DMSO (10 mL)and heated at 120° C. for 12 h. The crude reaction mixture was partlypurified by ion exchange chromatography, using a SCX column. The desiredproduct was eluted from the column using 7M NH3/MeOH and fractions wereevaporated to dryness. The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 10% 3M ammonia/MeOH inDCM. Pure fractions were evaporated to dryness to afford the desiredcompound (0.230 g, 17.67%) as a white solid.

1HNMR (700.03 MHz, CDCl3) δ: 1.48-1.53 (1H, m), 1.57-1.68 (2H, m),1.74-1.83 (1H, m), 2.34-2.40 (1H, m), 2.66-2.70 (1H, m), 2.97-3.02 (1H,m), 3.23-3.27 (1H, m), 3.83-3.87 (1H, m), 3.46-3.50 (3H, m), 3.85 (3H,s), 6.49 (2H, d), 7.89 (2H, d). MS: m/z 261 (MH+).

Example 152N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(1-methylpiperidin-4-yl)pyrazine-2-carboxamide

Trimethylaluminium (2 M in toluene, 1.73 ml, 3.46 mmol) was addeddropwise to a stirred suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (247 mg, 1.00 mmol)and methyl 5-(1-methylpiperidin-4-yl)pyrazine-2-carboxylate (235 mg,1.00 mmol) in anhydrous toluene (5.00 ml) at room temperature. Theresulting solution was stirred at 60° C. for 18 h. The reaction mixturewas quenched into methanol (100 mL) and treated with HCl (2M aqueoussolution, to pH7 or lower) and the crude product was purified by ionexchange chromatography, using a SCX column. The desired product waseluted from the column using 7M NH3/MeOH. At this point a white solidprecipitated from the eluent. The precipitate was collected by suctionfiltration and dried under vacuum to afford the product (90 mg, 20%) asa cream solid. The filtrate was concentrated and a second sample ofproduct was obtained by crystallisation from methanol to afford thetitle compound (93 mg, 21%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.80-1.89 (4H, m), 1.98-2.04 (2H, m), 2.22(3H, s), 2.83-2.90 (7H, m), 3.73 (6H, s), 6.33 (1H, t), 6.43 (2H, d),6.50 (1H, d), 8.73 (1H, d), 9.18 (1H, d), 10.27 (1H, s), 12.27 (1H, s).MS: m/z 451 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0013 μM.

Methyl 5-(1-methylpiperidin-4-yl)pyrazine-2-carboxylate used as startingmaterial was prepared as follows:

Sodium triacetoxyborohydride (530 mg, 2.50 mmol) was added to methyl5-(piperidin-4-yl)pyrazine-2-carboxylate (221 mg, 1.00 mmol),formaldehyde (37% aqueous solution, 1.50 ml, 20.00 mmol) and acetic acid(0.11 ml, 2.00 mmol) in methanol (5.00 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 18 h. The reactionmixture was quenched with water (5 mL) and the crude product waspurified by ion exchange chromatography, using a SCX column. The desiredproduct was eluted from the column using 7M NH3/MeOH and evaporated todryness to afford methyl5-(1-methylpiperidin-4-yl)pyrazine-2-carboxylate (239 mg, 100%) as ayellow waxy solid. This was used directly with no further purification.

1H NMR (399.9 MHz, CDCl3) δ 1.92-1.99 (4H, m), 2.07-2.13 (2H, m), 2.34(3H, s), 2.79-2.87 (1H, m), 2.99-3.03 (2H, m), 4.03 (3H, s), 8.61 (1H,d), 9.21 (1H, d). MS: m/z 236 (MH+).

Methyl 5-(piperidin-4-yl)pyrazine-2-carboxylate used as startingmaterial was prepared as follows:

Hydrogen chloride (4M in 1,4-dioxane, 0.37 ml, 1.48 mmol) was added tomethyl5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]pyrazine-2-carboxylate(120 mg, 0.37 mmol) in MeOH (3.70 ml). The resulting solution wasstirred at ambient temperature for 24 h. The crude product was purifiedby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and evaporated to drynessto afford methyl 5-(piperidin-4-yl)pyrazine-2-carboxylate (83 mg, 100%)as a pale yellow solid. This was used directly with no furtherpurification.

1H NMR (399.9 MHz, CDCl3) δ 1.76-1.86 (2H, m), 1.92-1.97 (2H, m), 2.80(2H, d), 2.97-3.05 (1H, m), 3.23-3.27 (2H, m), 4.04 (3H, s), 8.61 (1H,d), 9.22 (1H, d), NH not observed.

MS: m/z 222 (MH+).

Methyl5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]pyrazine-2-carboxylateused as starting material was prepared as follows:

Palladium, 10% on carbon (21 mg, 0.20 mmol) and methyl5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrazine-2-carboxylate(183 mg, 0.57 mmol) in ethanol (5.73 mL) was stirred under an atmosphereof hydrogen at ambient temperature and atmospheric pressure for 6 h. Thereaction mixture was filtered through celite and concentrated underreduced pressure to give a yellow oil. The crude product was purified bysilica column chromatography, eluting with a gradient of 0 to 50% EtOAcin isohexane. Pure fractions were evaporated to dryness to afford methyl5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]pyrazine-2-carboxylate(126 mg, 68%) as a yellow oil.

1H NMR (DMSO, 399.99 MHz) δ1.43 (9H, s), 1.58-1.68 (2H, m), 1.89 (2H,d), 2.88 (2H, s), 3.07-3.14 (1H, m), 3.92 (3H, s), 4.07-4.11 (2H, m),8.78 (1H, d), 9.13 (1H, d). MS: m/z 322 (MH+).

Methyl5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrazine-2-carboxylateused as starting material was prepared as follows:

Saturated aqueous sodium hydrogen carbonate solution (5.00 ml) was addedto methyl 5-chloropyrazine-2-carboxylate (173 mg, 1.00 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(371 mg, 1.20 mmol), palladium(II) acetate (11 mg, 0.05 mmol) andtriphenylphosphine (52 mg, 0.20 mmol) in 1,2-dimethoxyethane (5.00 ml)at 25° C. under nitrogen. The resulting mixture was stirred at 80° C.for 4 h. The reaction mixture was diluted with water (50 mL) and washedwith EtOAc (50 mL). The aqueous layer was adjusted to pH 1 using HCl (2Maqueous solution) and extracted with EtOAc (2×50 mL). The combinedorganics were dried over MgSO₄ and concentrated under reduced pressureto afford5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrazine-2-carboxylicacid (305 mg, 100%) as a yellow solid. This was used directly in thenext reaction, with no further purification.

1H NMR (DMSO, 399.9 MHz) δ1.45 (9H, s), 2.64 (2H, d), 3.58 (2H, t), 4.13(2H, d), 7.02 (1H, s), 9.01 (1H, d), 9.12 (1H, d), 13.40 (1H, br s). MS:m/z 306 (MH+).

Example 153N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxamide

Trimethylaluminium (2M in toluene, 1.74 ml, 3.48 mmol) was addeddropwise to a stirred suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (343 mg, 1.39 mmol)and methyl5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate (324 mg,1.39 mmol) in anhydrous toluene (6.94 ml) at ambient temperature. Theresulting solution was then stirred at 60° C. for 18 h. The reactionmixture was quenched into methanol (100 mL) and treated with HCl (2Maqueous solution, to pH7 or lower) and purified by ion exchangechromatography, using a SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and evaporated to dryness to afford impureproduct. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (152 mg, 24%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 2.33 (3H, s), 2.63-2.64 (4H, m), 2.86-2.89(4H, m), 3.16 (2H, s), 3.73 (6H, s), 6.33 (1H, s), 6.43-6.43 (2H, m),6.50 (1H, s), 7.04 (1H, s), 8.96 (1H, s), 9.17 (1H, s), 10.26 (1H, s),12.28 (1H, s). MS: m/z 449 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00082 μM.

Methyl 5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylateused as starting material was prepared as follows:

Sodium triacetoxyborohydride (749 mg, 3.53 mmol) was added to methyl5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxylate (310 mg, 1.41mmol), formaldehyde (37% aqueous solution, 2.10 ml, 28.30 mmol) andacetic acid (0.16 ml, 2.83 mmol) in methanol (7.00 ml) at 25° C. Theresulting solution was stirred at ambient temperature for 18 h. Thereaction mixture was quenched with saturated aqueous NaHCO₃ solution (5mL), diluted with methanol (10 mL) and the crude product was purified byion exchange chromatography, using a SCX column. The desired product waseluted from the column using 7M NH3/MeOH and evaporated to dryness toafford the desired compound (324 mg, 98%) as a tan waxy solid.

This was used directly with no further purification.

1H NMR (399.9 MHz, CDCl3) δ 2.44 (3H, s), 2.69-2.75 (4H, m), 3.23-3.25(2H, m), 4.03 (3H, s), 6.89-6.91 (1H, m), 8.79 (1H, d), 9.20 (1H, d).MS: m/z 234 (MH+).

Methyl 5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxylate used asstarting material was prepared as follows:

Hydrogen chloride (4M in 1,4-dioxane, 1.57 ml, 6.29 mmol) was added tomethyl5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrazine-2-carboxylate(502 mg, 1.57 mmol) in methanol (15.70 ml) at room temperature Theresulting solution was stirred at ambient temperature for 18 h. Thereaction mixture was diluted with water (20 mL) and the crude productpurified by ion exchange chromatography, using a SCX column. The desiredproduct was eluted from the column using 7M NH3/MeOH and evaporated todryness to afford the desired compound (316 mg, 92%) as a yellow solid.This was used directly with no further purification.

1H NMR (399.9 MHz, DMSO-d6) δ 2.47-2.54 (2H, m, partially obscured bysolvent peak), 2.94 (2H, t), 3.49 (2H, q), 3.92 (3H, s), 7.09-7.11 (1H,m), 9.00 (1H, d), 9.12 (1H, d), NH not observed. MS: m/z 261(M+MeCN+H+).

Methyl5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrazine-2-carboxylateused as starting material was prepared as outlined in Example 152.

Example 154N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide was prepared following theprocedure as for Example 155, but starting with ethyl4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.525 g, 2 mmol),5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol)and 2M trimethylaluminium (2.5 ml, 5.0 mmol in toluene). The crudemixture was chromatographed on a SCX column, eluting with 7N ammonia inmethanol. Fractions containing product were combined and evaporated togive an oil. The oil was suspended in dichloromethane (20 ml) andproduct slowly crystallised out. This was filtered to give the titlecompound (0.465 g, 50.2%).

1H NMR (399.9 MHz, DMSO-d6) δ 1.04-1.05 (6H, m), 1.92 (2H, s), 2.20-2.25(2H, m), 2.80-2.82 (1H, m), 2.81-2.84 (1H, m), 2.87 (4H, s), 3.71-3.74(2H, m), 3.73 (6H, s), 6.33 (1H, t), 6.40 (1H, s), 6.42 (2H, d), 6.95(2H, d), 7.89 (2H, d), 10.30 (1H, s). MS: m/z 464 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00075 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 155N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]benzamide

A 2M solution of trimethylaluminium (2.500 mL, 5.00 mmol) in toluene,was added dropwise to a stirred suspension of ethyl4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (0.643 g, 2 mmol) and5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol)in toluene (10 mL) at room temperature. The solution was then heated at60° C. for 18 h. The reaction mixture was cooled and quenched withmethanol (15 ml) and 2N hydrochloric acid (5 ml). The crude reactionmixture was purified by ion exchange chromatography on a SCX column,eluting with 7N ammonia in methanol. The appropriate fractions wereevaporated to give an oil. The crude product was purified by silicacolumn chromatography, eluting with a gradient of 0 to 10% 2.5Nammonia/MeOH in DCM. Pure fractions were evaporated to dryness toafford, on crystallisation from DCM/diethyl ether, the title compound(0.322 g, 33.7%) as a cream solid.

1HNMR (500.13 MHz, DMSOd+CD3COOD @ 373K) δ: 1.16 (6H, d), 2.34 (3H, s),2.48-2.55 (2H, m), 2.66 (2H, t), 2.88 (4H, s), 3.69-3.75 (2H, m), 3.73(3H, s), 6.28-6.92 (2H, m), 6.47-6.49 (2H, m), 6.92 (2H, d), 7.85 (2H,d). MS: m/z 478 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00045 μM.

Ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate used as startingmaterial was prepared as follows:

Sodium triacetoxyborohydride (5.30 g, 25.00 mmol) was added to ethyl4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (2.62 g, 10 mmol), andacetic acid (1.145 mL, 20.00 mmol) in methanol (15 mL) at 25° C. Theresulting solution was stirred at ambient temperature for 18 h. Thereaction mixture was quenched with saturated NaHCO₃ (15 mL) to pH7 andthe crude product was purified by ion exchange chromatography, using aSCX column. The desired product was eluted from the column using 7MNH3/MeOH and evaporated to dryness to afford an oil. The crude productwas purified by silica column chromatography, eluting with a gradient of0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to affordethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (1.960 g, 70.9%)as a yellow oil. MS: m/z 277 (MH+).

Ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate used as startingmaterial was prepared as follows: (2S,6R)-2,6-dimethylpiperazine (6.85g, 60.00 mmol) was added to ethyl-4-fluorobenzoate (2.20 mL, 15 mmol),in DMSO (40 mL) and warmed to 120° C. under nitrogen. The resultingsolution was stirred at 120° C. for 20 h. The reaction mixture wascooled and the solvent evaporated. The crude product was purified bysilica column chromatography, eluting with a gradient of 0 to 10%methanol in dichloromethane containing 1% 0.880 ammonia. Pure fractionswere evaporated to dryness to afford ethyl4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (2.83 g, 71.9%) as abrown oil, which solidified on standing.

1H NMR (399.9 MHz, CDCl3) δ 1.15 (6H, d), 1.37 (3H, t), 2.38 (1H, d),2.41 (1H, d), 2.96-3.04 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q),6.84-6.87 (2H, m), 7.89-7.93 (2H, m). MS: m/z 263 (MH+).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 156N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-methyl-1,4-diazepan-1-yl)benzamidewas prepared following the procedure as for Example 115, but startingfrom of methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate (0.372 g, 1.5mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.371 g,1.5 mmol) and 2M trimethylaluminium in toluene (1.875 ml, 3.75 mmol).The crude product was purified by silica column chromatography, elutingwith a gradient of 0 to 10% 2.5M ammonia/MeOH in DCM. Pure fractionswere evaporated to dryness and the residual oil crystallised fromDCM/diethyl ether to afford the title compound (0.142 g, 20.42%) as awhite solid. 1HNMR (500.13 MHz, DMSOd6+CD3COOD @ 373K) δ: 2.08-2.15 (2H,m), 2.69 (3H, s), 2.88 (4H, s), 3.11 (2H, t), 3.19-3.24 (2H, m), 3.56(2H, t), 3.72 (3H, s), 3.74 (2H, t), 6.30 (1H, d), 3.32 (1H, s), 6.49(2H, s), 6.79 (2H, d), 7.86 (2H, d). MS: m/z 464 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00081 μM.

Methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate used as starting materialwas prepared as follows:

1-Methyl-1,4-diazepane (15.07 g, 132.00 mmol) was added to methyl4-fluorobenzoate (7.76 mL, 60 mmol) in DMA (150 mL). The resultingsolution was stirred at 100° C. for 40 h. The reaction mixture wasevaporated and quenched with 2M sodium hydroxide (50 ml). This wasextracted with DCM (3×50 ml). The combined organic extracts were washedwith saturated brine (50 ml), dried over MgSO₄, filtered and evaporatedto dryness. The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Purefractions were evaporated to dryness to afford methyl4-(4-methyl-1,4-diazepan-1-yl)benzoate (3.59 g, 24.10%) as a tan waxysolid.

1H NMR (399.9 MHz, CDCl3) δ 1.95 (2H, q), 2.31 (3H, s), 2.48 (2H, d),2.63-2.65 (2H, m), 3.47 (2H, t), 3.54-3.56 (2H, m), 3.78 (3H, s),6.56-6.59 (2H, m), 7.79-7.83 (2H, m).

Example 157N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3-dimethylaminopyrrolidin-1-yl)pyrazine-2-carboxamide

N,N-dimethylpyrrolidin-3-amine (114 mg, 1.00 mmol) was added to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(136 mg, 0.35 mmol) in anhydrous dimethylsulfoxide (1.75 ml) at 25° C.The resulting solution was stirred at room temperature for 20 mins. Thereaction mixture was diluted with methanol (5.00 ml) and the crudeproduct was purified by ion exchange chromatography, using a SCX column.The desired product was eluted from the column using 7M NH3/MeOH andfractions were evaporated to dryness to afford impure product as a brownoil. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (130 mg, 80%) as a white solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 1.86 (1H, t), 2.16-2.21 (1H, m) 2.23 (6H,s), 2.83-2.85 (1H, m), 2.88 (4H, s), 3.25-3.29 (1H, m), 3.45-3.54 (1H,m), 3.72 (6H, s), 3.73-3.79 (1H, m), 3.81-3.86 (1H, m), 6.33 (1H, t),6.42 (2H, d), 6.46 (1H, s), 8.01 (1H, d), 8.71 (1H, d), 9.73 (1H, s),12.17 (1H, s). MS: m/z 466 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0024 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 1585-(3-diethylaminopyrrolidin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

N,N-diethylpyrrolidin-3-amine (142 mg, 1.00 mmol) was added to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(136 mg, 0.35 mmol) in anhydrous dimethylsulfoxide (1.75 ml) at 25° C.The resulting solution was stirred at room temperature for 50 mins. Thereaction mixture was diluted with methanol (5.00 ml) and the crudeproduct was purified by ion exchange chromatography, using a SCX column.The desired product was eluted from the column using 7M NH3/MeOH andfractions were evaporated to dryness to afford impure product as a browndry film. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the title compound (141 mg, 82%) as a white solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 0.99 (6H, t), 1.80-1.90 (1H, m), 2.17-2.23(1H, m), 2.56-2.68 (4H, m), 2.88 (4H, s), 3.20-3.26 (1H, m), 3.34-3.41(1H, m), 3.43-3.50 (1H, m), 3.72 (6H, s), 3.73-3.78 (1H, m) 3.82-3.87(1H, m), 6.33 (1H, t), 6.42 (2H, d), 6.46 (1H, s), 8.01 (1H, d), 8.71(1H, d), 9.73 (1H, s), 12.17 (1H, s). MS: m/z 494 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0029 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 159N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-ethylpiperidin-4-yl)benzamide

A 2M solution of trimethylaluminium in toluene (0.413 mL, 0.83 mmol),was added drop-wise to a suspension of methyl4-(1-ethylpiperidin-4-yl)benzoate (0.082 g, 0.33 mmol) and5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.082 g, 0.33 mmol)in toluene (2 mL) at room temperature. The solution was then heated at60° C. for 18 h. The reaction mixture was cooled, quenched with methanol(2 ml) and 2N hydrochloric acid (1 ml). The reaction mixture waspurified by ion exchange chromatography, using a SCX column. The desiredproduct was eluted from the column using 7M NH3/MeOH and fractions wereevaporated to dryness. The crude product was purified by preparativeHPLC, using decreasingly polar mixtures of water (containing 1% NH3) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the title compound (0.058 g, 38.0%) as awhite solid.

1H NMR (500.13 MHz, DH4OAcDMSO-d6) δ 1.21 (3H, t), 1.26 (2H, s),1.84-1.93 (1H, m), 1.95-2.04 (2H, m), 2.77 (2H, t), 2.89 (4H, s), 2.94(2H, q), 3.34-3.40 (2H, m), 3.72 (6H, s), 6.30 (1H, d), 6.35 (1H, d),6.41 (2H, d), 7.34 (2H, d), 7.89 (2H, d). MS: m/z 463 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00097 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 4-(1-ethylpiperidin-4-yl)benzoate used as starting material wasprepared as follows: Sodium triacetoxyborohydride (0.397 g, 1.88 mmol)was added portion-wise to acetaldehyde (0.168 mL, 3.00 mmol), methyl4-(piperidin-4-yl)benzoate, HCl (0.192 g, 0.75 mmol) and sodium acetate(0.062 g, 0.75 mmol) in methanol (5 mL) at room temperature. Theresulting solution was stirred at room temperature for 18 h. Thereaction mixture was quenched with saturated NaHCO₃ (3 mL) to pH7 andthe crude product was purified by ion exchange chromatography, using aSCX column. The desired product was eluted from the column using 7MNH3/MeOH and evaporated to dryness to afford an oil. The crude productwas purified by silica column chromatography, eluting with a gradient of0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to affordmethyl 4-(1-ethylpiperidin-4-yl)benzoate (0.082 g, 44.2%) as acolourless oil. MS: m/z 248 (MH+).

Example 160N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-[3-(methoxymethyl)piperazin-1-yl]pyrimidine-5-carboxamide

Trimethylaluminium (2M in toluene, 1.596 mL, 3.19 mmol) was addeddropwise to a solution of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (314 mg, 1.27 mmol)and methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate(338 mg, 1.27 mmol) in toluene (6.35 mL) at 25° C. The resulting mixturewas stirred at 60° C. for 18 h under nitrogen. The reaction mixture wasadded to methanol (100 mL) and treated with HCl (2N aqueous solution,until pH was 7 or lower). The crude product was purified by ion exchangechromatography, using a SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and fractions were evaporated to dryness toafford the crude product as a yellow dry film. The crude product waspurified by preparative HPLC, using decreasingly polar mixtures of water(containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(348 mg, 57%) as a white solid.

1H NMR (399.9 MHz, CDCl₃) δ 2.72-2.77 (2H, m), 2.82-2.92 (5H, m),2.97-3.04 (2H, m), 3.24-3.28 (1H, m), 3.30 (3H, s), 3.35-3.38 (1H, m),3.69 (6H, s), 4.61 (2H, d), 6.25-6.28 (3H, m), 6.61 (1H, s), 8.73 (1H,s), 8.76 (2H, s), 9.6 (1H, s). MS: m/z 482 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0043 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate usedas starting material was prepared as follows:

A solution of methyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.74mmol) in DCM (4.70 mL) was added to a stirred solution of2-(methoxymethyl)piperazine (226 mg, 1.74 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (0.752 mL, 4.35 mmol) in DCM (4.00mL) at 25° C. under nitrogen. The resulting solution was stirred at roomtemperature for 6 h. The reaction mixture was concentrated and dilutedwith MeOH. The resulting mixture was filtered. The filtrate was purifiedby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and fractions wereevaporated to dryness to afford methyl2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (346 mg,75%) as a yellow solid. This was used directly with no furtherpurification.

1H NMR (399.9 MHz, CDCl₃) δ 2.72-2.79 (2H, m), 2.84-2.90 (1H, m),2.99-3.07 (2H, m), 3.25-3.30 (1H, m), 3.31 (3H, s), 3.38-3.42 (1H, m),3.80 (3H, s), 4.61-4.68 (2H, m), 8.76 (2H, s). MS: m/z 267 (MH+)

2-(Methoxymethyl)piperazine used as starting material was prepared asfollows: 1,4-Dibenzyl-2-(methoxymethyl)piperazine (1.578 g, 5.08 mmol)and palladium (10% on carbon, 0.163 g, 1.53 mmol) in ethanol (50.8 ml)were stirred under an atmosphere of hydrogen at room temperature for 3days. The reaction mixture was filtered through celite, washing withethanol. The resulting mixture was evaporated to dryness to afford crudeproduct. The crude product was purified by ion exchange chromatography,using a SCX column. The desired product was eluted from the column using7M NH3/MeOH and fractions were evaporated to dryness to afford2-(methoxymethyl)piperazine (0.559 g, 84%) as a yellow oil. This wasused directly without further purification.

1H NMR (399.9 MHz, CDCl₃) δ 2.37-2.43 (1H, m), 2.65-2.76 (2H, m),2.78-2.86 (3H, m), 2.89-2.92 (1H, m), 3.14-3.18 (1H, m), 3.24-3.27 (1H,m), 3.27 (3H, s).

1,4-Dibenzyl-2-(methoxymethyl)piperazine used as starting material wasprepared as follows: Sodium hydride (0.857 g, 21.42 mmol) was addedportionwise to stirred Et₂O (23.0 ml) at 25° C. under nitrogen. Asolution of (1,4-dibenzylpiperazin-2-yl)methanol (1.411 g, 4.76 mmol) inDMF (8.0 ml) was added portionwise under nitrogen. The resultingsuspension was stirred at room temperature for 1 h. A solution of methyliodide (0.454 ml, 7.28 mmol) in Et₂O (7.0 ml) was added dropwise to thereaction mixture at 10° C., under nitrogen. The resulting mixture wasstirred at room temperature for 21 h. The reaction mixture was quenchedwith water (35 mL and extracted with Et₂O (3×50 mL). The organic layerswere combined and washed with water (50 mL), dried over MgSO₄, filteredand evaporated to afford 1,4-dibenzyl-2-(methoxymethyl)piperazine (1.580g, 107%) as a yellow oil. This was used directly without furtherpurification.

1H NMR (399.9 MHz, DMSO-d₆) δ 2.10-2.23 (3H, m), 2.44-2.48 (1H, m),2.57-2.63 (3H, m), 3.21 (3H, s), 3.35-3.39 (1H, m), 3.44 (2H, d),3.60-3.63 (1H, m), 3.95-3.99 (1H, m), 7.20-7.34 (10H, m). 1H obscured bywater peak. MS: m/z 311 (MH+)

Example 161N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(3-methylaminopyrrolidin-1-yl)pyrazine-2-carboxamide

Hydrogen chloride (4M in dioxane, 0.57 mL, 2.26 mmol) was added totert-butylN-[1-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methylcarbamate(312 mg, 0.57 mmol) in methanol (2.80 mL) at 25° C. The resultingsolution was stirred at room temperature for 48 h. The reaction wasincomplete and further hydrogen chloride (4M in dioxane, 0.28 mL, 1.12mmol) was added and the solution was stirred at room temperature for afurther 16 h. The reaction mixture was diluted with MeOH (5 ml) and thecrude product was purified by ion exchange chromatography, using a SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand fractions were evaporated to dryness to afford impure product. Thecrude product was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (101 mg, 39%) as a white solid.

1H NMR (399.9 MHz, CDCl₃) δ 1.85-1.93 (1H, m), 2.14-2.22 (1H, m), 2.43(3H, s), 2.84-2.92 (4H, m), 3.39-3.42 (2H, m), 3.51-3.57 (1H, m),3.63-3.68 (2H, m), 3.70 (6H, s), 6.25-6.26 (1H, m), 6.30 (2H, d), 6.43(1H, s), 7.69 (1H, d), 8.85 (1H, d), 9.65 (1H, s). MS: m/z 452 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.003 μM.

tert-butylN-[1-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methylcarbamateused as starting material was prepared as follows: A solution oftert-butyl N-methyl-N-pyrrolidin-3-ylcarbamate (200 mg, 1.00 mmol) indioxane (0.75 ml) was added to a stirred solution of5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(136 mg, 0.35 mmol) in dioxane (0.75 ml) and NMP (0.25 ml) at 25° C. Theresulting solution was stirred at room temperature for 24 h. Thereaction was incomplete so N-ethyl-N-propan-2-ylpropan-2-amine (0.06 ml,0.35 mmol) was added and the solution was stirred at room temperaturefor a further 17 h. The reaction mixture was diluted with MeOH (5 ml)and the crude product was purified by ion exchange chromatography, usinga SCX column. The desired product was eluted from the column using 7MNH3/MeOH and fractions were evaporated to dryness to afford impureproduct (312 mg, 162%) as a yellow oil. This was used directly with nofurther purification.

MS: m/z 552 (MH+)

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 162N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxamide

Trimethylaluminium (2 M in toluene, 1.168 ml, 2.34 mmol) was addeddropwise to a suspension of5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (231 mg, 0.93 mmol)and methyl 2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxylate (220 mg,0.93 mmol) in anhydrous toluene (4.671 ml) at 25° C. The resultingsolution was stirred at 60° C. for 2 h. The reaction mixture was pouredinto methanol (100 mL), acidified with 2M HCl and the crude product waspurified by ion exchange chromatography, using a SCX column. The desiredproduct was eluted from the column using 7M NH3/MeOH. The crude productwas purified by preparative HPLC, using decreasingly polar mixtures ofwater (containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(166 mg, 39%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.80-1.88 (2H, m), 1.94 (2H, d), 1.98-2.03(2H, m), 2.21 (3H, s), 2.80-2.85 (3H, m), 2.89 (4H, s), 3.73 (6H, s),6.33 (1H, t), 6.42 (2H, d), 6.49 (1H, s), 9.20 (2H, s), 11.04 (1H, s),12.24 (1H, s). MS: m/z 451 (MH+).

Mean of n=4, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.036 μM.

Methyl 2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxylate used asstarting material was prepared as follows:

Sodium triacetoxyborohydride (532 mg, 2.51 mmol) was added to methyl2-(piperidin-4-yl)pyrimidine-5-carboxylate (222 mg, 1.00 mmol),formaldehyde (37% aqueous solution, 1.50 ml, 20.07 mmol) and acetic acid(0.115 ml, 2.01 mmol) in methanol (4.994 ml) at 25° C. The resultingsolution was stirred at ambient temperature for 3 days. The reactionmixture was diluted with methanol (20 mL) and the crude product waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford methyl2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxylate (223 mg, 94%) as acream waxy solid. This was used directly with no further purification.

1H NMR (399.9 MHz, DMSO-d6) δ 1.77-1.88 (2H, m), 1.95 (2H, d), 2.00-2.07(2H, m), 2.22 (3H, s), 2.83-2.90 (3H, m), 3.91 (3H, s), 9.19 (2H, s).MS: m/z 236 (MH+).

Methyl 2-piperidin-4-ylpyrimidine-5-carboxylate used as startingmaterial was prepared as follows:

Hydrogen chloride (4M in 1,4-dioxane, 3.04 ml, 12.15 mmol) was added toa stirred suspension of methyl2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrimidine-5-carboxylate (976mg, 3.04 mmol) in methanol (15.20 ml) at 25° C. The resulting solutionwas stirred at ambient temperature for 18 hours. The reaction mixturewas purified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford methyl2-(piperidin-4-yl)pyrimidine-5-carboxylate (600 mg, 89%) as a yellowsolid. This was used directly with no further purification.

1H NMR (399.9 MHz, DMSO-d6) δ 1.63-1.73 (2H, m), 1.86-1.89 (2H, m),2.58-2.65 (2H, m), 2.96-3.07 (3H, m), 3.91 (3H, s), 9.19 (2H, s), NH notobserved. MS: m/z 222 (MH+).

Methyl2-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]pyrimidine-5-carboxylateused as starting material was prepared as follows:

Methyl2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate(960 mg, 3.01 mmol) and palladium, 10% on carbon (96 mg, 0.09 mmol) inethanol (10 ml) and ethyl acetate (40.0 ml) were stirred under anatmosphere of hydrogen at atmospheric pressure and ambient temperaturefor 18 h. The reaction mixture was filtered through celite, washing withmethanol, ethyl acetate and dichloromethane and concentrated underreduced pressure to give methyl2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrimidine-5-carboxylate (966mg, 100%) as a yellow oil, which crystallised on standing. This was useddirectly with no further purification.

1H NMR (399.9 MHz, DMSO-d6) δ 1.42 (9H, s), 1.61-1.70 (2H, m), 1.97 (2H,d), 2.91 (2H, s), 3.10-3.16 (1H, m), 3.91 (3H, s), 4.03 (2H, d), 9.20(2H, s). MS: 322 m/z (MH+).

Methyl2-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrimidine-5-carboxylateused as starting material was prepared as follows:

(Trimethylsilyl)diazomethane, 2M in hexanes (4.19 ml, 8.38 mmol) wasadded dropwise to2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylicacid (1.28 g, 4.19 mmol) in toluene (12 ml) and methanol (3.00 ml) at25° C. over a period of 2 mins under nitrogen. The resulting solutionwas stirred at ambient temperature for 2 hours. The reaction mixture wasquenched with the dropwise addition of acetic acid until bubblingceased, then the reaction mixture was diluted with EtOAc (100 mL) andwater (100 mL). The organic layer was removed and the aqueous furtherextracted with EtOAc (2×50 mL). The combined organics were washed withsodium hydrogen carbonate solution (100 mL), water (100 mL), brine (100mL) and dried over MgSO₄, filtered and evaporated to afford methyl2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate(1.182 g, 88%) as a yellow solid. This was used directly with no furtherpurification.

1H NMR (399.9 MHz, DMSO-d6) δ 1.44 (9H, s), 2.63-2.66 (2H, m), 3.56 (2H,t), 3.92 (3H, s), 4.16 (2H, d), 7.38 (1H, s), 9.21 (2H, s). MS: m/z 320(MH+).

2-[1-[(2-Methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrimidine-5-carboxylicacid used as starting material was prepared as follows:

Saturated aqueous sodium hydrogen carbonate solution (25.00 ml) wasadded to methyl 2-chloropyrimidine-5-carboxylate (0.863 g, 5 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.855 g, 6.00 mmol), palladium(II) acetate (0.056 g, 0.25 mmol) andtriphenylphosphine (0.262 g, 1.00 mmol) in 1,2-dimethoxyethane (25.00ml) at 25° C. under nitrogen. The resulting mixture was stirred at 80°C. for 4 h. The cooled reaction mixture was taken up in water (50 mL),washed with EtOAc (50 mL) and then the aqueous layer was acidified topH1 with 2N HCl. The aqueous layer was extracted with EtOAc (3×25 mL)and the combined organics washed with brine, dried over MgSO₄ andconcentrated under reduced pressure to afford2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylicacid (1.280 g, 84%) as a yellow solid. This was used directly with nofurther purification.

1H NMR (399.9 MHz, DMSO-d6) δ 1.44 (9H, s), 2.65 (2H, q), 3.56 (2H, t),4.15 (2H, m), 7.36 (1H, s), 9.18 (2H, s), 13.6 (1H, s). MS: m/z 304(M−H).

5-[2-(3,5-Dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 163N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-methyl-1,4-diazepan-1-yl)pyrazine-2-carboxamide

1-methyl-1,4-diazepane (0.20 ml, 1.60 mmol) was added to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solutionwas stirred at room temperature for 1 h. The reaction mixture wasdiluted with MeOH (5 ml) and the crude product was purified by ionexchange chromatography, using a SCX column. The desired product waseluted from the column using 7M NH3/MeOH and fractions were evaporatedto dryness to afford crude product as an orange dry film. The crudeproduct was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (296 mg, 79%) as a white solid.

1H NMR (399.9 MHz, CDCl₃) δ 1.95-2.01 (2H, m), 2.32 (3H, s), 2.53 (2H,t), 2.66 (2H, t), 2.84-2.92 (4H, m), 3.65-3.75 (2H, m), 3.70 (6H, s),3.81-3.86 (2H, m), 6.26 (1H, t), 6.29 (2H, d), 6.45 (1H, s), 7.82 (1H,d), 8.83 (1H, d), 9.65 (1H, s). One NH peak not observed.

MS: m/z 466 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0018 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 164N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-prop-2-enyl-1,4-diazepan-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-prop-2-enyl-1,4-diazepan-1-yl)benzamidewas prepared using the same procedure as for Example 159, but startingfrom ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.288 g, 1 mmol,5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol)and a 2M solution of trimethylaluminium (1.250 mL, 2.50 mmol) intoluene. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford a gum, which solidified on trituration with DCM/Etherto afford the title compound (0.071 g, 14.50%).

1H NMR (399.9 MHz, CDCl₃) δ 1.87-1.93 (2H, m), 2.53 (2H, t), 2.68 (2H,t), 2.86-2.91 (4H, m), 3.07 (2H, d), 3.43 (2H, t), 3.48 (1H, t), 3.50(1H, d), 3.71 (6H, s), 5.11-5.13 (1H, m), 5.12-5.17 (1H, m), 5.79-5.86(1H, m), 6.28 (1H, t), 6.33 (2H, d), 6.59 (2H, d), 7.75 (2H, d), 9.26(1H, s). MS: m/z 490 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00078 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate used as starting materialwas prepared as follows: 3-Bromoprop-1-ene (0.433 mL, 5.00 mmol) wasadded to a stirred solution of ethyl 4-(1,4-diazepan-1-yl)benzoate(1.242 g, 5 mmol) and DIPEA (2.183 mL, 12.50 mmol) in dichloromethane(20 mL). The reaction mixture was stirred under nitrogen at roomtemperature for 24 h. This was diluted with dichloromethane (20 mL),washed with water (2×25 ml) and saturated sodium chloride solution (20ml), dried over MgSO₄, filtered and evaporated to dryness. The crudeproduct was purified by silica column chromatography, eluting with agradient of 0 to 5% 2.5M ammonia/MeOH in DCM. Pure fractions wereevaporated to dryness to afford ethyl4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.700 g, 48.5%) as a yellow oil.

1H NMR (399.9 MHz, CDCl₃) δ 1.36 (3H, t), 1.94-2.00 (2H, m), 2.57-2.60(2H, m), 2.75 (1H, d), 2.77-2.77 (1H, m), 3.10-3.12 (2H, m), 3.54-3.64(4H, m), 4.31 (2H, q), 5.11-5.15 (1H, m), 5.11-5.19 (1H, m), 5.78-5.91(1H, m), 6.62-6.66 (2H, m), 7.87-7.90 (2H, m). MS: m/z 289 (MH+).

Ethyl 4-(1,4-diazepan-1-yl)benzoate used as starting material wasprepared as follows: Ethyl 4-fluorobenzoate (11.01 mL, 75 mmol) and1,4-diazepane (30.0 g, 300.00 mmol) in DMSO (150 mL) warmed to 100° C.under nitrogen. The resulting solution was stirred at 100° C. for 24 h.The reaction mixture was cooled and evaporated to dryness. The reactionmixture was quenched with 2M NaOH (150 mL), extracted with EtOAc (3×75mL), the organic layer was washed with saturated brine (100 ml), driedover MgSO₄, filtered and evaporated to afford ethyl4-(1,4-diazepan-1-yl)benzoate (17.43 g, 94%) as a colourless oil.

1H NMR (399.9 MHz, CDCl3) δ 1.27-1.31 (3H, m), 1.71 (1H, s), 1.79-1.85(2H, m), 2.74 (1H, d), 2.74 (1H, d), 2.95 (1H, d), 2.96 (1H, d), 3.51(2H, t), 3.56 (2H, t), 4.21-4.27 (2H, m), 6.56-6.60 (2H, m), 7.80-7.83(2H, m). MS: m/z 249 (MH+).

Example 1654-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide

4-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamidewas prepared using the same procedure as for Example 159, but startingfrom ethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate (0.288 g, 1 mmol,5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol)and a 2M solution of trimethylaluminium (1.250 mL, 2.50 mmol) intoluene. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford a gum which solidified on trituration with DCM/Etherto afford the title compound (0.165 g, 33.7%).

1H NMR (500.13 MHz, DMSOd6+CD3COOD @ 373K) δ 0.32-0.36 (2H, m),0.41-0.47 (2H, m), 1.84-1.90 (2H, m), 2.93-2.98 (1H, m), 2.76 (2H, t),2.87 (4H, s), 2.93 (2H, t), 3.50-3.58 (4H, m), 3.72 (6H, s), 6.29 (1H,s), 6.30-6.32 (1H, m), 6.39 (2H, d), 6.72 (2H, d), 7.81 (2H, d). MS: m/z490 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.000064 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Ethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate used as startingmaterial was prepared as follows:

A solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (0.621 g, 2.5 mmol),(1-ethoxycyclopropoxy)trimethylsilane (2.51 mL, 12.50 mmol) and aceticacid (0.286 mL, 5.00 mmol) in tetrahydrofuran (50 mL), methanol (5 mL)was treated with sodium cyanoborohydride (0.393 g, 6.25 mmol) at 20° C.The resulting solution was stirred at 60° C. for 18 h. The reactionmixture was cooled, filtered and evaporated to dryness. 1N HCl (40 ml)and water (60 ml) were added and the solution extracted with ethylacetate (3×50 ml). The aqueous layer was basified to pH 10 with solidpotassium carbonate and extracted with ethyl acetate (4×50 ml). Theorganic extracts washed with saturated NaCl (50 ml) and dried overMgSO₄, filtered and evaporated to dryness. The crude product waspurified by silica column chromatography, eluting with a gradient of 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to affordethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate (0.849 g, 118%) as acolourless oil.

1H NMR (399.9 MHz, CDCl₃) δ 0.33 (1H, t), 0.34-0.35 (1H, m), 0.36-0.41(1H, m), 0.37-0.40 (1H, m), 1.29 (3H, t), 1.74-1.79 (1H, m), 1.84-1.90(2H, m), 2.69 (2H, t), 2.86 (2H, t), 3.47 (2H, t), 3.49 (2H, t), 4.24(2H, q), 6.58 (1H, d), 6.60 (1H, s), 7.81-7.84 (2H, m). MS: m/z 289(MH+) (ESI+).

Example 166N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-yl-1,4-diazepan-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-yl-1,4-diazepan-1-yl)benzamidewas prepared using the same procedure as for Example 159, but startingfrom ethyl 4-(4-isopropyl-1,4-diazepan-1-yl)benzoate (0.212 g, 0.73mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.181 g,0.73 mmol) and a 2M solution of trimethylaluminium (0.913 ml, 1.83 mmol)in toluene. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford a gum which solidified on trituration with DCM/Etherto afford the title compound (0.154 g, 42.9%) as a cream solid.

1H NMR (500.13 MHz, DMSOd6+CD3COOD @ 373K) δ 1.00 (6H, s), 1.85-1.90(2H, m), 2.64 (2H, t) 2.80-2.85 (2H, m), 2.88 (4H, s), 2.94-3.01 (1H,m), 3.53-3.59 (4H, m), 3.72 (6H, s), 6.29 (1H, s), 6.30-6.32 (1H, m),6.40 (2H, d), 6.73 (2H, d), 7.81 (2H, d). MS: m/z 492 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0007 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Ethyl 4-(4-isopropyl-1,4-diazepan-1-yl)benzoate used as startingmaterial was prepared as follows:

A solution of ethyl 4-fluorobenzoate (0.293 mL, 2 mmol) and1-isopropyl-1,4-diazepane (0.539 mL, 4.00 mmol) in dimethylsulfoxide (10mL), was heated at 120° C. for 18 h. The reaction mixture was dilutedwith water (75 ml) and extracted with ethyl acetate (3×25 ml). Theextracts were washed with saturated sodium chloride solution (50 ml),dried over MgSO₄, filtered and evaporated to dryness. The crude productwas purified by silica column chromatography, eluting with a gradient of0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to affordethyl 4-(4-isopropyl-1,4-diazepan-1-yl)benzoate (0.212 g, 36.5%) as ayellow oil.

1H NMR (399.9 MHz, CDCl3) δ 0.92 (6H, d), 1.28 (3H, t), 1.80-1.86 (2H,m), 2.46 (2H, t), 2.69 (2H, t), 2.81-2.89 (1H, m), 3.51 (4H, t), 4.24(2H, q), 6.58 (2H, d), 7.81 (2H, d). MS: m/z 291 (MH+) (ESI+).

Example 167N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-propan-2-yl-1,4-diazepan-1-yl)pyrazine-2-carboxamide

1-isopropyl-1,4-diazepane (228 mg, 1.60 mmol) was added to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solutionwas stirred at room temperature for 2 hours. The reaction was incompleteso the temperature was increased to 60° C. and the reaction mixture wasstirred for a further 2 h. The reaction was still incomplete so thereaction mixture was stirred for a further 18 h at room temperature. Thereaction mixture was diluted with MeOH (5 ml) and the crude product waspurified by ion exchange chromatography, using a SCX column. The desiredproduct was eluted from the column using 7M NH3/MeOH and fractions wereevaporated to dryness to afford crude product as an orange dry film. Thecrude product was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 1% NH3) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound (167 mg, 42%) as a pale yellow solid.

1H NMR (399.9 MHz, CDCl₃) δ 0.93 (6H, d), 1.83-1.89 (2H, m), 2.54 (2H,t), 2.72 (2H, t), 2.82-2.92 (5H, m), 3.70 (6H, s), 3.73-3.76 (4H, m),6.26 (1H, d), 6.29 (2H, d), 6.43 (1H, s), 7.81 (1H, d), 8.82 (1H, d),9.64 (1H, s). One NH signal not observed. MS: m/z 494 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00063 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 168N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxamide

Trimethylaluminium (0.751 ml, 1.50 mmol) was added dropwise to a stirredsuspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (148mg, 0.60 mmol) and ethyl5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxylate (178 mg, 0.60mmol) in toluene (3.002 ml) at 25° C. The resulting solution was stirredat 60° C. for 18 h. The cooled reaction mixture was added to methanol(50 mL) and treated with HCL (2M aqueous solution, to pH7 or below) andpurified by ion exchange chromatography, using a SCX column. The desiredproduct was eluted from the column using 7M NH3/MeOH and evaporated todryness to afford impure material. The crude product was purified bypreparative HPLC, using decreasingly polar mixtures of water (containing1% NH3) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (123 mg, 41%) asa yellow solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.95-0.96 (6H, m), 1.79-1.85 (2H, m),2.54-2.56 (2H, m), 2.72 (2H, m), 2.85 (4H, s), 2.88 (1H, m), 3.42-3.48(4H, m), 3.72 (6H, s), 5.86 (1H, d), 6.33 (1H, s), 6.34 (1H, s), 6.41(2H, d), 7.78 (1H, d), 10.14 (1H, s), 12.00 (1H, s). MS: m/z 498 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0015 μM.

Ethyl 5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxylate used asstarting material was prepared as follows:

Sodium triacetoxyborohydride (396 mg, 1.87 mmol) was added portionwiseto ethyl 5-(1,4-diazepan-1-yl)thiophene-2-carboxylate (190 mg, 0.75mmol) and acetic acid (0.086 ml, 1.49 mmol) in acetone (1.917 ml) atroom temperature. The resulting solution was stirred at ambienttemperature for 18 h under nitrogen. The reaction mixture wasconcentrated and diluted with water (200 mL) and basified with 2M NaOH.The aqueous was extracted with diethyl ether (3×100 mL) and washedsequentially with water (200 mL) and saturated brine (200 mL). Theorganic layer was dried over MgSO₄, filtered and evaporated to afforddesired product ethyl5-(4-isopropyl-1,4-diazepan-1-yl)thiophene-2-carboxylate (181 mg, 82%).This was used directly with no further purification.

1H NMR (399.9 MHz, CDCl₃) δ 0.99-1.01 (6H, m), 1.33 (3H, t), 1.89-1.95(2H, m), 2.59-2.62 (2H, m), 2.75-2.77 (2H, m), 2.88-2.95 (1H, m),3.48-3.52 (4H, m), 4.27 (2H, q), 5.77-5.78 (1H, d), 7.54 (1H, d). MS:m/z 297 (MH+).

Ethyl 5-(1,4-diazepan-1-yl)thiophene-2-carboxylate used as startingmaterial was prepared as follows:

Palladium(II) acetate (52.1 mg, 0.23 mmol) followed by sodiumtert-butoxide (624 mg, 6.49 mmol) was added to a stirred solution ofethyl 5-bromothiophene-2-carboxylate (1090 mg, 4.64 mmol),homopiperazine (511 mg, 5.10 mmol) and(rac)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (289 mg, 0.46mmol) in toluene (20 mL) at 25° C. under nitrogen. The resultingsuspension was stirred at 110° C. for 3 h. The cooled reaction mixturewas diluted with MeOH and the crude product was purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and fractions containing the desiredproduct were evaporated to dryness to afford impure product as a brownoil. The crude product was purified by silica column chromatography,eluting with a gradient of 0 to 5% 7N NH3/MeOH in DCM and then 0 to 3%NH3/MeOH in DCM. Pure fractions were evaporated to dryness to affordethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylate (195 mg, 17%) asa yellow oil.

1H NMR (399.9 MHz, CDCl₃) δ 1.33 (3H, t), 1.89-1.95 (2H, m), 2.88 (2H,t), 3.03-3.06 (2H, m), 3.49-3.54 (2H, m), 3.57 (2H, t), 4.27 (2H, q),5.80 (1H, d), 7.54 (1H, d) NH not observed. MS: m/z 255 (MH+).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 169N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-ethyl-1,4-diazepan-1-yl)pyrazine-2-carboxamide

1-ethyl-1,4-diazepane (205 mg, 1.60 mmol) was added to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solutionwas stirred at room temperature for 2 h. The reaction was incomplete sothe temperature was increased to 60° C. and the reaction mixture wasstirred for a further 15 mins. The reaction mixture was diluted withMeOH (5 ml) and the crude product was purified by ion exchangechromatography, using a SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and fractions were evaporated to dryness toafford crude product as an orange dry film. The crude product waspurified by preparative HPLC, using decreasingly polar mixtures of water(containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(228 mg, 59%) as a white solid.

1H NMR (399.9 MHz, CDCl₃) δ 1.00 (3H, t), 1.91-1.97 (2H, m), 2.50 (2H,q), 2.56 (2H, t), 2.72 (2H, t), 2.84-2.91 (4H, m), 3.69 (6H, s),3.67-3.71 (2H, m), 3.79-3.82 (2H, m), 6.25 (1H, t), 6.29 (2H, d), 6.45(1H, s), 7.81 (1H, d), 8.83 (1H, d), 9.68 (1H, s). MS: m/z 480 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0027 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 170N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-ethyl-1,4-diazepan-1-yl)benzamide

N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-ethyl-1,4-diazepan-1-yl)benzamidewas prepared using the same procedure as for Example 159, but startingfrom ethyl 4-(4-ethyl-1,4-diazepan-1-yl)benzoate (0.502 g, 1.4 mmol),5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.346 g, 1.40 mmol)and A 2M solution of trimethylaluminium (1.750 mL, 3.50 mmol) intoluene. The crude product was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford a gum which solidified on trituration with DCM/Etherto afford the title compound (0.171 g, 25.6%) as a white solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 1.00 (3H, t), 1.89 (2H, d), 2.53 (2H, d),2.73 (4H, s), 2.87 (4H, s), 3.49-3.54 (2H, m), 3.54-3.58 (2H, m), 3.73(6H, s), 6.33 (1H, t), 6.42 (3H, d), 6.73 (2H, d), 7.87 (2H, d), 10.17(1H, s), 12.04 (1H, s). MS: m/z 478 (MH+) (ESI+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00071 μM.

Ethyl 4-(4-ethyl-1,4-diazepan-1-yl)benzoate used as starting materialwas prepared as follows:

A solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (0.621 g, 2.5 mmol),acetaldehyde (0.701 mL, 12.50 mmol) and acetic acid (0.286 mL, 5.00mmol) in tetrahydrofuran (30 mL), methanol (3 mL) was treated withsodium cyanoborohydride (0.393 g, 6.25 mmol) at 20° C. The resultingsolution was stirred at 60° C. for 18 h. The reaction mixture was cooledand extra amount of acetaldehyde (2.146 mL, 38 mmol) and sodiumtriacetoxyborohydride (1.060 g, 5.00 mmol) were added. The reaction wasstirred at room temperature for 18 h. The reaction mixture was filteredand evaporated to dryness. The residue was dissolved in 2N HCl (5 ml)and methanol (20 ml). The solution of crude product was purified by ionexchange chromatography, using a SCX column. The desired product waseluted from the column using 7M NH3/MeOH and pure fractions wereevaporated to dryness to afford ethyl4-(4-ethyl-1,4-diazepan-1-yl)benzoate (0.526 g, 76%)

1H NMR (399.9 MHz, CDCl₃) δ 1.07 (3H, t), 1.36 (3H, t), 1.90-2.05 (2H,m), 2.52-2.61 (2H, m), 2.70-2.77 (2H, m), 3.54 (2H, t), 3.57 (2H, t),4.29-4.34 (2H, m), 6.63-6.67 (2H, m), 7.86-7.90 (2H, m). MS: m/z 277(MH+).

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Example 171N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (1.25 ml, 2.50 mmol) was added dropwise to a stirredsuspension of methyl2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (265 mg, 1.00mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (248 mg,1.00 mmol) in toluene (5.01 ml) at 25° C. The resulting solution wasstirred at 60° C. for 18 h. The cooled reaction mixture was quenchedinto methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7or lower) and purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The crude productwas purified by preparative HPLC, using decreasingly polar mixtures ofwater (containing 1% NH3) and MeCN as eluents. Fractions containingdesired product still contained an impurity, so they were concentratedto dryness and purified by crystallisation from MeCN to afford the titlecompound (104 mg, 22%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.99 (3H, t), 1.82-1.87 (2H, m), 2.48 (2H,q, partially obscured by DMSO peak), 2.52-2.57 (2H, m, partiallyobscured by DMSO peak), 2.71 (2H, m), 2.87 (4H, s), 3.72 (6H, s), 3.82(2H, t), 3.87 (2H, t), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 8.88(2H, s), 10.56 (1H, s), 12.13 (1H, s). MS: m/z 480 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0092 μM.

Methyl 2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate used asstarting material was prepared as follows:

A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16mmol) in dichloromethane (4.00 mL) was added to a stirred solution of1-ethyl-1,4-diazepane (149 mg, 1.16 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) indichloromethane (4.00 mL) at 25° C. The resulting solution was stirredat ambient temperature for 18 h. The reaction mixture was evaporated todryness and redissolved in MeOH (20 mL) and the crude product waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford methyl2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (268 mg, 87%) as acream oil which crystallised on standing. This was used directly with nofurther purification.

1H NMR (399.9 MHz, DMSO-d6) δ 0.98 (3H, t), 1.81-1.87 (2H, m), 2.45-2.50(2H, m), 2.55 (2H, m), 2.70-2.72 (2H, m), 3.81 (3H, s), 3.82 (2H, q),3.86-3.89 (2H, m), 8.79 (2H, s). MS: m/z 265 (MH+).

1-Ethyl-1,4-diazepane used as starting material was prepared as follows:

Lithium aluminum hydride (38.2 ml, 38.19 mmol) was added to1-(1,4-diazepan-1-yl)ethanone (1.697 g, 11.93 mmol) in THF (59.7 ml) at0° C. under nitrogen. The resulting solution was stirred at ambienttemperature for 1 h and then at 60° C. for 1 h. The cooled reactionmixture was poured onto ice (500 mL), acidified with HCl (2M aqueoussolution) and purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford 1-ethyl-1,4-diazepane (0.610 g, 40%)as a yellow liquid. This was used directly with no further purification.

1H NMR (399.9 MHz, CDCl3) δ 1.07 (3H, t), 1.74-1.80 (2H, m), 2.58 (2H,q), 2.64-2.70 (4H, m), 2.89-2.95 (4H, m).

Example 172N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-5-(4-prop-2-enyl-1,4-diazepan-1-yl)pyrazine-2-carboxamide

1-Prop-2-enyl-1,4-diazepane (224 mg, 1.60 mmol) was added to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solutionwas stirred at room temperature for 3 h. The reaction mixture wasdiluted with MeOH (5 ml) and the crude product was purified by ionexchange chromatography, using a SCX column. The desired product waseluted from the column using 7M NH3/MeOH and fractions were evaporatedto dryness to afford crude product as an orange oil. The crude productwas purified by preparative HPLC, using decreasingly polar mixtures ofwater (containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(271 mg, 69%) as a yellow solid.

1H NMR (399.9 MHz, CDCl₃) δ 1.91-1.97 (2H, m), 2.57 (2H, t), 2.72 (2H,t), 2.84-2.91 (4H, m), 3.06 (2H, d), 3.70 (6H, s), 3.74-3.83 (4H, m),5.07-5.13 (2H, m), 5.73-5.83 (1H, m), 6.25 (1H, t), 6.29 (2H, d), 6.43(1H, s), 7.82 (1H, d), 8.83 (1H, d), 9.64 (1H, s). MS: m/z 492 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0034 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 173N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (1.19 ml, 2.38 mmol) was added dropwise to a stirredsuspension of methyl2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (265 mg,0.95 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (235mg, 0.95 mmol) in toluene (4.76 ml) at 25° C. The resulting solution wasstirred at 60° C. for 18 h. The cooled reaction mixture was quenchedinto methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7or lower) and purified by ion exchange chromatography, using an SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The crude productwas purified by preparative HPLC, using decreasingly polar mixtures ofwater (containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(81 mg, 17%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.94-0.95 (6H, m), 1.78 (2H, m), 2.51-2.54(2H, m, partially obscured by DMSO peak), 2.67-2.74 (3H, m), 2.87 (4H,s), 3.73 (6H, s), 3.82 (4H, t), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H,s), 8.88 (2H, s), 10.55 (1H, s), 12.13 (1H, s). MS: m/z 494 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.018 μM.

Methyl 2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate usedas starting material was prepared as follows:

A solution of methyl 2-chloropyrimidine-5-carboxylate (209 mg, 1.21mmol) in dichloromethane (4.00 ml) was added to a stirred solution of1-propan-2-yl-1,4-diazepane (172 mg, 1.21 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (0.523 ml, 3.02 mmol) indichloromethane (4.00 ml) at 25° C. The resulting solution was stirredat ambient temperature for 18 h. The reaction mixture was evaporated todryness and redissolved in MeOH (20 mL) and the crude product waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford methyl2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (267 mg,79%) as a cream oil which crystallised on standing. This was useddirectly with no further purification.

1H NMR (399.9 MHz, DMSO-d6) δ 0.92-0.94 (6H, m), 1.74-1.80 (2H, m), 2.71(2H, t), 2.82-2.89 (1H, m), 3.81 (3H, s), 3.80-3.85 (4H, m), 8.78-8.78(2H, m), 1x (2H, m) obscured by DMSO peak. MS: m/z 279 (MH+).

1-Propan-2-yl-1,4-diazepane used as starting material was prepared asfollows:

Benzyl 4-propan-2-yl-1,4-diazepane-1-carboxylate (3.00 g, 10.85 mmol)and palladium, 10% on carbon (0.289 g, 2.71 mmol) in ethanol (54.3 ml)were stirred under an atmosphere of hydrogen at atmospheric pressure andambient temperature for 18 h. The reaction mixture was filtered throughcelite, washing with ethanol, methanol and dichloromethane and thefiltrate concentrated under reduced pressure to afford1-propan-2-yl-1,4-diazepane (1.54 g, 100%) as a yellow liquid. This wasused directly with no further purification.

1H NMR (399.9 MHz, CDCl3) δ 1.00-1.02 (6H, m), 1.69-1.74 (2H, m), 1.94(1H, br s), 2.63-2.68 (4H, m), 2.87-2.94 (5H, m).

Benzyl 4-propan-2-yl-1,4-diazepane-1-carboxylate used as startingmaterial was prepared as follows:

Sodium triacetoxyborohydride (5.79 g, 27.32 mmol) was added portionwiseto benzyl 1,4-diazepane-1-carboxylate (2.56 g, 10.93 mmol) and aceticacid (1.251 mL, 21.85 mmol) in acetone (5.00 mL) at room temperature.The resulting solution was stirred at ambient temperature for 18 h undernitrogen. The reaction mixture was concentrated and diluted with water(200 mL) and basified with 2M NaOH. The aqueous was extracted withdiethyl ether (3×100 mL) and washed sequentially with water (200 mL) andsaturated brine (200 mL). The organic layer was dried over MgSO₄,filtered and evaporated to afford the desired product (3.00 g, 99%).This was used directly with no further purification.

1H NMR (399.9 MHz, DMSO-d6) δ 0.92-0.95 (6H, m), 1.63-1.69 (2H, m), 2.60(2H, t), 2.80-2.88 (1H, m), 3.38-3.45 (4H, m), 5.09 (2H, s), 7.29-7.40(5H, m), one (2H, m) obscured by solvent peak. MS: m/z 277 (MH+).

Example 1745-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

1-Cyclopropyl-1,4-diazepane, 2HCl (205 mg, 0.96 mmol) was added to5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide(310 mg, 0.80 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.48 ml,2.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution wasstirred at room temperature for 24 h. The reaction was incomplete so thetemperature was increased to 80° C. and the reaction mixture was stirredfor a further 3 h. The reaction mixture was diluted with MeOH (5 ml).The crude product was purified by ion exchange chromatography, using aSCX column. The desired product was eluted from the column using 7MNH3/MeOH and fractions were evaporated to dryness to afford crudeproduct as a brown oil. The crude product was purified by preparativeHPLC, using decreasingly polar mixtures of water (containing 1% NH3) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the title compound (277 mg, 70%) as ayellow solid.

1H NMR (399.9 MHz, CDCl₃) δ 0.32-0.37 (2H, m), 0.38-0.43 (2H, m),1.75-1.80 (1H, m), 1.86-1.92 (2H, m), 2.74 (2H, t), 2.83-2.92 (6H, m),3.70 (6H, s), 3.70-3.77 (4H, m), 6.26 (1H, t), 6.29 (2H, d), 6.42 (1H,s), 7.82 (1H, d), 8.83 (1H, d), 9.64 (1H, s). MS: m/z 492 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0037 μM.

5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamidewas prepared as shown in Example 105.

Example 175N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-prop-2-enyl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (1.35 ml, 2.70 mmol) was added dropwise to a stirredsuspension of methyl2-(4-prop-2-enyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (300 mg,1.09 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (268mg, 1.09 mmol) in toluene (5.43 ml) at 25° C. The resulting solution wasstirred at 60° C. for 18 h. The cooled reaction mixture was quenchedinto methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7or lower) and purified by ion exchange chromatography, using a SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The crude productwas purified by preparative HPLC, using decreasingly polar mixtures ofwater (containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(220 mg, 41%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.82-1.88 (2H, m), 2.53-2.57 (2H, m,partially obscured by DMSO peak), 2.71 (2H, t), 2.88 (4H, s), 3.08 (2H,d), 3.73 (6H, s), 3.83 (2H, t), 3.86-3.88 (2H, m), 5.10-5.13 (1H, m),5.17 (1H, d), 5.77-5.87 (1H, m), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H,s), 8.89 (2H, s), 10.56 (1H, s), 12.13 (1H, s). MS: m/z 492 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.007 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 2-(4-prop-2-enyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate usedas starting material was prepared as follows:

A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16mmol) in dichloromethane (4.00 mL) was added to a stirred solution of1-prop-2-enyl-1,4-diazepane (163 mg, 1.16 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (0.501 mL, 2.90 mmol) indichloromethane (4.00 mL) at 25° C. The resulting solution was stirredat ambient temperature for 18 h. The reaction mixture was evaporated todryness and redissolved in MeCN (20 mL) and the crude product waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford the desired compound (304 mg, 95%) as acream oil which crystallised on standing. This was used directly with nofurther purification.

1H NMR (399.9 MHz, DMSO-d6) δ 1.81-1.87 (2H, m), 2.55 (2H, m), 2.70-2.72(2H, m), 3.06-3.09 (2H, m), 3.81 (3H, s), 3.80-3.89 (4H, m), 5.09-5.13(1H, m), 5.13-5.19 (1H, m), 5.76-5.86 (1H, m), 8.79 (2H, d). MS: m/z 277(MH+).

1-Prop-2-enyl-1,4-diazepane used as starting material was prepared asfollows: To a solution of tert-butyl 1-homopiperazinecarboxylate (9.73mL, 50 mmol) in dichloromethane (250 mL) was added PS-TBD resin (40 g,100 mmol) and 3-bromoprop-1-ene (4.33 mL, 50 mmol) dropwise at 25° C.The mixture was stirred for 2 h. The PS-TBD was filtered off and thefiltrate evaporated to dryness, redissolved in MeOH/EtOAc (1:9) and thenfiltered through a short silica column. The filtrate obtained wasevaporated to dryness, treated with TFA (20 ml) and then stirred at roomtemperature for 1 h. The reaction mixture was evaporated to dryness andredissolved in MeOH (50 mL) and the crude product was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 7M NH3/MeOH and evaporated to dryness toafford 1-prop-2-enyl-1,4-diazepane (4.07 g, 58.0%) as a pale yellow oil.

1H NMR (399.902 MHz, CDCl3) δ 1.70 (m, 2H), 1.98 (s, 1H), 2.59 (m, 4H),2.85 (m, 4H), 3.06 (m, 2H), 5.07 (m, 2H), 5.81 (m, 1H)

Example 176N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxamide

Trimethylaluminium (1.35 ml, 2.70 mmol) was added dropwise to a stirredsuspension of methyl2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (270 mg, 1.08mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (267 mg,1.08 mmol) in toluene (5.39 ml) at 25° C. The resulting solution wasstirred at 60° C. for 18 h. The cooled reaction mixture was quenchedinto methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7or lower) and purified by ion exchange chromatography, using a SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The crude productwas purified by preparative HPLC, using decreasingly polar mixtures ofwater (containing 1% NH3) and MeCN as eluents. Fractions containing puredesired compound were evaporated to dryness to afford the title compound(136 mg, 27%) as a cream solid. The fractions containing impure productwere concentrated and purified by crystallisation from MeCN to affordthe title compound (56.0 mg, 11%) as a beige solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.86-1.92 (2H, m), 2.27 (3H, s), 2.64 (2H,t), 2.88 (4H, s), 3.73 (6H, s), 3.81 (2H, t), 3.89 (2H, t), 6.33 (1H,t), 6.41-6.45 (3H, m), 8.89 (2H, s), 10.57 (1H, s), 12.13 (1H, s). 2Hobscured by DMSO peak. MS: m/z 466 (MH+).

Mean of n=1, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0058 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate used asstarting material was prepared as follows:

A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16mmol) in dichloromethane (4.00 mL) was added to a stirred solution of1-methyl-1,4-diazepane (0.144 mL, 1.16 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) indichloromethane (4.00 mL) at 25° C. The resulting solution was stirredat ambient temperature for 18 h. The reaction mixture was evaporated todryness and redissolved in MeOH (20 mL) and the crude product waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford methyl2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (274 mg, 94%) asa white solid. This was used directly with no further purification.

1H NMR (399.9 MHz, DMSO-d6) δ 1.86-1.89 (2H, m), 2.26 (3H, s), 2.49-2.54(2H, m, partially obscured by DMSO peak), 2.62-2.64 (2H, m), 3.81 (3H,s), 3.80-3.84 (2H, m), 3.89-3.91 (2H, m), 8.79 (2H, d). MS: m/z 251(MH+)

Example 1772-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrimidine-5-carboxamide

Trimethylaluminium (1.402 ml, 2.80 mmol) was added dropwise to a stirredsuspension of methyl2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (310 mg,1.12 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (277mg, 1.12 mmol) in toluene (5.61 ml) at 25° C. The resulting solution wasstirred at 60° C. for 18 h. The cooled reaction mixture was quenchedinto methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7or lower) and purified by ion exchange chromatography, using a SCXcolumn. The desired product was eluted from the column using 7M NH3/MeOHand evaporated to dryness to afford impure product. The crude productwas purified by preparative HPLC, using decreasingly polar mixtures ofwater (containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(8.00 mg, 1%) as a cream solid. Some impure fractions were combined andconcentrated to dryness and purified by crystallisation from MeCN toafford the title compound (51 mg, 9%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d6) δ 0.31 (2H, m), 0.41-0.44 (2H, m), 1.84-1.89(3H, m), 2.71 (2H, t), 2.88 (4H, s), 3.73 (6H, s), 3.81-3.87 (4H, m),6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 8.89 (2H, s), 10.55 (1H, s),12.14 (1H, s), 2H obscured by DMSO peak. MS: m/z 492 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0073 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate usedas starting material was prepared as follows:

A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16mmol) in dichloromethane (4.00 mL) was added to a stirred solution of1-cyclopropyl-1,4-diazepane (247 mg, 1.16 mmol) andN-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) indichloromethane (4.00 mL) at 25° C. The resulting solution was stirredat ambient temperature for 18 h. The reaction mixture was evaporated todryness and redissolved in MeOH (20 mL) and the crude product waspurified by ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 7M NH3/MeOH andevaporated to dryness to afford methyl2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (312 mg,97%) as a cream solid. This was used directly with no furtherpurification.

1H NMR (399.9 MHz, DMSO-d6) δ 0.28-0.31 (2H, m), 0.40-0.45 (2H, m),1.80-1.84 (2H, m), 1.85-1.89 (1H, m), 2.71 (2H, m), 2.85-2.88 (2H, m),3.81 (3H, s), 3.82-3.88 (4H, m), 8.79 (2H, s). MS: m/z 277 (MH+)

Example 178N-[5-[2-[3-(methylcarbamoyl)phenyl]ethyl]-2H-pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide

A 2M solution of trimethylaluminium (0.936 mL, 1.87 mmol) in toluene,was added drop-wise to a stirred suspension of3-(2-(5-amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide (0.183 g, 0.75mmol) and methyl 4-(4-methylpiperazin-1-yl)benzoate (0.176 g, 0.75 mmol)in toluene (5 mL) at room temperature. The solution was then stirred at60° C. for 18 h. The reaction mixture was cooled, poured into methanol(5 ml) and acidified with 2N HCl (15 ml). The crude product was purifiedby ion exchange chromatography, using a SCX column. The desired productwas eluted from the column using 7M NH3/MeOH and pure fractions wereevaporated to dryness to afford an oil. The crude product was purifiedby preparative HPLC, using decreasingly polar mixtures of water(containing 1% NH3) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the title compound(0.109 g, 32.6%) as a white solid.

1H NMR (399.9 MHz, DMSO-d6) δ 1.88 (3H, s), 2.23 (3H, s), 2.45 (4H, t),2.87-3.02 (4H, m), 3.40 (4H, t), 6.39 (1H, s), 6.97 (2H, d), 7.37 (1H,s), 7.38 (2H, t), 7.65-7.67 (1H, m), 7.75 (1H, s), 7.90 (2H, d), 8.36(1H, d), 10.36 (1H, s). MS: m/z 447 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0011 μM.

3-(2-(5-Amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide used as startingmaterial was prepared as follows:

1.8M LDA in THF (30.0 mL, 54.00 mmol) was added to tetrahydrofuran (60mL) and cooled to −78° C. Acetonitrile (2.82 mL, 54.00 mmol) was addeddrop-wise over 15 mins. A solution of methyl3-(3-(methylcarbamoyl)phenyl)propanoate (2.99 g, 13.5 mmol) intetrahydrofuran (10 ml) was added. The resulting mixture stirred at −78°C. for 10 mins. The reaction mixture was warmed to 5° C. and stirred for30 mins, hydrazine hydrochloride (3.70 g, 54.00 mmol) and ethanol (60.0mL) were added and the reaction mixture heated at 80° C. for 18 h. Thereaction mixture was cooled and evaporated to dryness. The residue wasdissolved in methanol (50 ml) and the crude product was purified by ionexchange chromatography, using a SCX column. The desired product waseluted from the column using 7M NH3/MeOH fractions were evaporated todryness to afford an oil. The crude product was purified by silicacolumn chromatography, eluting with a gradient of 0 to 10% MeOH in DCM.Pure fractions were evaporated to dryness to afford3-(2-(5-amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide (0.450 g, 13.64%)as a yellow oil.

1H NMR (399.9 MHz, DMSO-d₆) δ 2.73-2.79 (4H, m), 2.89 (1H, d), 3.18 (3H,d), 4.09 (1H, d), 5.19 (1H, s), 7.35 (1H, s), 7.35-7.37 (1H, m),7.63-7.66 (1H, m), 7.72 (1H, s), 8.38 (1H, d)—1 proton not seen. MS: m/z245 (MH+).

Methyl 3-(3-(methylcarbamoyl)phenyl)propanoate used as starting materialwas prepared as follows:

A solution of (E)-methyl 3-[3-(methylcarbamoyl)phenyl]prop-2-enoate(3.77 g, 17.20 mmol) and 10% palladium on carbon (0.458 g, 0.43 mmol) ina mixture of ethanol (100 mL) and DMF (10.00 mL) was stirred at roomtemperature for 18 h under a balloon of hydrogen. The reaction mixturewas filtered through celite and evaporated to dryness to afford methyl3-(3-(methylcarbamoyl)phenyl)propanoate (3.05 g, 80%) as a white solid.MS: m/z 222 (MH+).

(E)-methyl 3-[3-(methylcarbamoyl)phenyl]prop-2-enoate used as startingmaterial was prepared as follows:

A solution of 3-formyl-N-methylbenzamide (2.9 g, 17.77 mmol) and methyl2-triphenylphosphoranylideneacetate (8.91 g, 26.66 mmol) indichloromethane (85 mL), was stirred at room temperature for 18 h. Thereaction mixture was evaporated to dryness. The crude product waspurified by silica column chromatography, eluting with a gradient of 0to 10% MeOH in DCM. Pure fractions were evaporated to dryness to affordimpure product. Repurified by silica column chromatography, eluting witha gradient of 50 to 100% EtOAc in hexanes. Pure fractions wereevaporated to dryness to afford (E)-methyl3-[3-(methylcarbamoyl)phenyl]prop-2-enoate (3.77 g, 97%).

1H NMR (399.9 MHz, CDCl₃) δ 3.02-3.03 (3H, m), 3.81 (3H, s), 6.34 (1H,s), 6.51 (1H, s), 7.42-7.48 (2H, m), 7.61-7.66 (1H, m), 7.67 (1H, d),7.74-7.76 (1H, m), 7.93 (1H, t).

3-Formyl-N-methylbenzamide used as starting material was prepared asfollows:

A 2M solution of methylamine in THF (44 mL, 5 eq, 87.5 mmol) was addedto methyl 3-formylbenzoate (2.875 g, 1 eq, 17.5 mmol) in dry THF (65ml). The reaction mixture was cooled to −50° C. under nitrogen and a 2Msolution of trimethylaluminium in toluene (22 ml, 2.5 eq, 43.75 mmol)was added slowly over 15 mins. The reaction mixture was allowed to warmslowly to room temperature and stirred for 18 h. The reaction mixturewas quenched with a 20% w/v solution of potassium sodium tartrate inwater (50 ml). This was extracted with ethyl acetate (2×100 ml) andwashed with water (50 ml), saturated sodium chloride solution (50 ml),dried over MgSO₄ and evaporated under reduced pressure to give a gum.The crude product was purified by silica column chromatography, elutingwith a gradient of 0 to 2.5% methanol in DCM. Pure fractions werecombined and evaporated to afford 3-formyl-N-methylbenzamide (1.6502 g,58%) as an off-white solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 2.78-2.85 (3H, m), 7.70-7.75 (1H, t),8.05-8.08 (1H, m), 8.04-8.09 (1H, m), 8.37-8.39 (1H, d), 8.63-8.70 (1H,s), 10.08 (1H, s). MS: m/z 164 (MH+).

Example 179N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(4-ethylpiperazin-1-yl)benzamide

Trimethylaluminium (2M in toluene, 1.51 mL, 3.02 mmol) was addeddropwise to 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine, HCl(345 mg, 1.21 mmol) and methyl 4-(4-ethylpiperazin-1-yl)benzoate (300mg, 1.21 mmol) in toluene (6.0 mL) at 25° C. The resulting solution wasstirred at 60° C. for 19 h under nitrogen. The reaction was incompleteand further trimethylaluminium (0.50 mL, 3.02 mmol) was added and thesolution was stirred at 60° C. for a further 4 h. The reaction mixturewas added to methanol (100 ml) and treated with HCl (2N aqueoussolution, until pH was 7 or lower). The crude product was purified byion exchange chromatography, using a SCX column. Some productcrystallised out of the pure fractions and was collected by vacuumfiltration to give the title compound (95 mg, 17%) as a white solid. Thefiltrate was evaporated to dryness to give a further sample of the titlecompound (115 mg, 20%) as a white solid. Impure fractions containing thedesired product were repurified by preparative HPLC, using decreasinglypolar mixtures of water (containing 1% NH3) and MeCN as eluents, toafford a third sample of the title compound (27 mg, 5%) as a whitesolid.

1H NMR (399.9 MHz, DMSO-d₆) δ 1.05 (3H, t), 2.38 (2H, q), 3.75 (6H, s),5.08 (2H, s), 5.67 (1H, s), 6.45 (1H, t), 6.60 (2H, d), 7.01 (2H, d),7.86 (2H, d). At approximately δ 2.5, 4H peak obscured by DMSO. Atapproximately δ 3.3, 4H peak obscured by H₂O. MS: m/z 466 (MH+)

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.00068 μM.

5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride, usedas starting material was prepared as in Example 12.

Methyl 4-(4-ethylpiperazin-1-yl)benzoate, used as starting material, wasprepared as follows: 1-Ethylpiperazine (3.68 mL, 29.0 mmol) was added tomethyl 4-fluorobenzoate (1.50 mL, 11.6 mmol) in dimethylsulfoxide (29.0mL) at 25° C. The resulting solution was stirred at 120° C. for 18 h.The reaction mixture was concentrated and diluted with EtOAc (50 mL) andwater (20 mL). NaOH (2N aqueous solution, 20 mL) was added and thelayers were separated and washed with EtOAc (40 mL). The organic layerswere combined and washed with water (40 mL) and saturated brine (40 mL).The organic layer was dried over magnesium sulphate, filtered andevaporated to afford the desired product (1.960 g, 68%). This was usedwithout further purification.

1H NMR (399.9 MHz, CDCl₃) δ 1.06 (3H, t), 2.40 (2H, q), 2.52 (4H, t),3.29 (4H, t), 3.79 (3H, s), 6.78-6.81 (2H, m), 7.83-7.86 (2H, m). MS:m/z 249 (MH+)

Example 180N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-ethylpiperazin-1-yl)benzamide

Trimethylaluminium (2M in toluene, 1.51 mL, 3.02 mmol) was addeddropwise to 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (299 mg,1.21 mmol) and methyl 4-(4-ethylpiperazin-1-yl)benzoate (300 mg, 1.21mmol) in toluene (6.0 mL) at 25° C. The resulting suspension was stirredat 60° C. for 24 h under nitrogen. The reaction mixture was added tomethanol (100 mL) and was treated with HCl (2N aqueous solution, untilthe pH was 7 or lower). The crude product was purified by ion exchangechromatography, using a SCX column. The desired product was eluted fromthe column using 7M NH3/MeOH and fractions were evaporated to dryness toafford impure product. The crude product was purified by silica columnchromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM.Pure fractions were evaporated to dryness to afford the title compound(288 mg, 51%) as a cream solid.

1H NMR (399.9 MHz, DMSO-d₆) δ 1.05 (3H, t), 2.38 (2H, q), 2.50 (4H, peakobscured by DMSO), 2.87 (4H, s), 3.26-3.29 (4H, m), 3.73 (6H, s), 6.33(1H, t), 6.42 (2H, d), 6.45 (1H, s), 6.96 (2H, d), 7.90 (2H, d), 10.29(1H, s), 12.07 (1H, s). MS: m/z 464 (MH+).

Mean of n=2, FGFR Kinase assay—Caliper Echo Dosing, IC₅₀ 0.0017 μM.

5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine, used as startingmaterial was prepared as indicated in Example 2.

Methyl 4-(4-ethylpiperazin-1-yl)benzoate, used as starting material, wasprepared as outlined in Example 179.

Enzyme Assays

FGFR Kinase Assay—Caliper

To determine inhibition of FGFR activity, kinase assays were conductedusing Caliper technology.

Kinase activity assays were performed in Greiner 384-well low volumeplates, with a total reaction volume of 12 ul per well. Finalconcentration of FGFR1 active kinase in each reaction well was 7.2 nM.The substrate for each assay was a custom peptide with fluorescent tag(13 amino acids in length, KKSRGDYMTMQIG with the fluorescene tag on thefirst K).

Compounds were serially diluted in 5% (v/v) DMSO, before being added toassay plates. The Enzyme (at 7.2 nM [final]) and Substrate (at 3.6 uM[final]) were added separately to the compound plates, in reactionbuffer [comprising: 50 mM MOPS (Sigma, Catalogue No. M1254)—pH 6.5,0.004% Triton (Sigma, Catalogue No. X-100), 2.4 mM DTT, 12 mM MgCl₂, 408uM ATP] resulting in a final DMSO concentration in the reaction mix of0.8%.

Assay plates were incubated at room temperature for 1.5 h, before thereaction was stopped with the addition of buffer [comprising: 100 mMHEPES—pH7.5, 0.033% Brij-35 (Sigma Catalogue No. B4184), 0.22% CaliperCoating Reagent #3 (Caliper Life Sciences Catalogue No. 760050), 88 mMEDTA, 5% DMSO]. Stopped assay plates were then read using the CaliperLabChip® LC3000 (which uses microfludics to measure a shift in mobilitybetween fluorescent labelled peptide and the FGFR1 kinase—phosphorylatedform of this peptide).

In the assay, compounds were tested at a range of concentrations. Themean data values for each concentration, along with untreated controlwells and 100% inhibition control wells were used to derive a plot ofinhibition against concentration. From this data, the IC50 value or apercentage inhibition value at fixed concentration may be determined.

Percentage inhibition at 1 uM, as expressed herein, is a calculatedvalue based on the curve fit that was generated experimentally. From thefitted curve plot, the effect of compound at a concentration of 1 uM wascalculated as a percentage inhibition. The IC₅₀ is the concentration ofcompound, which inhibits FGFR1 kinase activity by 50% in the context ofthis assay.

Results of FGFR Inhibition Tests for Examples

Example Activity class 3 A 4 A 5 A 6 A 7 A 8 A 9 A 13 B 14 B 15 A 16 B17 B 18 B 19 B 20 A Activity: A less than 0.3 μM B greater than 0.3 μMand less than 1 μM C greater than 1 μM and less than 30 μM Eg. Example14 is 612 nM.FGFR Kinase Assay—Caliper Echo Dosing

To determine inhibition of FGFR activity, kinase assays were conductedusing Caliper technology.

Kinase activity assays were performed in Greiner 384-well low volumeplates, with a total reaction volume of 12 ul per well. Finalconcentration of FGFR1 active kinase in each reaction well was 7.2 nM.The substrate for each assay was a custom peptide with fluorescent tag(13 amino acids in length, KKSRGDYMTMQIG with the fluorescene tag on thefirst K).

Compounds were dispensed directly in to assay plates using a LabcyteEcho 550 acoustic droplet ejection unit. Each well received 120 nl ofDMSO containing compound such that the final concentration of compoundin the assay prior to the addition of the stop solution ranged between30 uM and 30 pM. In addition to compounds each plate carried maximum andminimum control wells, the max wells contained 120 nl of DMSO and themin wells contained 120 nl of 10 mM staurosporine (LC Laboratories, MA01801, USA Catalogue No. S-9300). The Enzyme (at 7.2 nM [final]) andSubstrate (at 3.6 uM [final]) were added separately to the compoundplates, in reaction buffer [comprising: 50 mM MOPS (Sigma, Catalogue No.M1254)—pH 6.5, 0.004% Triton (Sigma, Catalogue No. X-100), 2.4 mM DTT,12 mM MgCl₂, 408 uM ATP] resulting in a final DMSO concentration in thereaction mix of 1%.

Assay plates were incubated at room temperature for 1.5 h, before thereaction was stopped with the addition of buffer [comprising: 100 mMHEPES—pH7.5, 0.033% Brij-35 (Sigma Catalogue No. B4184), 0.22% CaliperCoating Reagent #3 (Caliper Life Sciences Catalogue No. 760050), 88 mMEDTA, 5% DMSO]. Stopped assay plates were then read using the CaliperLabChip® LC3000 (which uses microfludics to measure a shift in mobilitybetween fluorescent labelled peptide and the FGFR1 kinase—phosphorylatedform of this peptide).

In the assay, compounds were tested at a range of concentrations. Themean data values for each concentration, along with untreated controlwells and 100% inhibition control wells were used to derive a plot ofinhibition against concentration. From this data, the IC50 value or apercentage inhibition value at fixed concentration may be determined.Percentage inhibition at 1 uM, as expressed herein, is a calculatedvalue based on the curve fit that was generated experimentally. From thefitted curve plot, the effect of compound at a concentration of 1 uM wascalculated as a percentage inhibition. The IC₅₀ is the concentration ofcompound, which inhibits FGFR1 kinase activity by 50% in the context ofthis assay. This value is calculated using a standard curve fittingsoftware package Origin™. Where compounds have been tested on more thanone occasion the IC₅₀ value is sited as a geometric mean.

FGFR Kinase Assay—Elisa

To determine inhibition of FGFR activity, kinase assays were conductedusing ELISA (Enzyme-Linked Immunosorbent Assay) technology.

Kinase activity assays were performed in 384-well polypropylene plates(Matrix, Catalogue No. 4311. Matrix are part of Thermo FisherScientific, 22 Friars Drive, Hudson, N.H. 03051, USA) with a totalvolume of 40 μl in each well. Each well was coated with 2 μg of polyEAYsubstrate (Sigma, Catalogue No. P3899) at 4° C. overnight. The plateswere then washed once with 100 μl PBS and once with 100 μl 50 mM HEPES(pH 7.4) prior to the addition of the kinase assay reagents. Reactionscontained His6-tagged FGFR kinase domain (FGFR kinase domain (aminoacids 458-765, C488A, C584S) N-terminally fused to a His6-tag and TEVcleavage site encoded by the following sequence;[MHHHHHHEFKGSTSLYKKAGSSENLYFQGA]. The final alanine denotes the start ofthe FGFR protein sequence. The resultant protein was expressed andpurified based on Mohammadi et al, Cell Vol 86, 577-587 (1996). Eachkinase reaction contained 0.1 ng His6-tagged FGFR kinase domain, 50 mMHEPES (pH 7.4), 0.1 mM Na₃VO₄, 0.1 mM DTT, 0.05% (v/v) Triton X100, 20mM MgCl₂, 160 μM ATP. Various concentrations of test compounds were eachadded in 5% (v/v) DMSO to yield a final assay DMSO concentration of1.25% (v/v). The kinase reactions were incubated at room temperature for45 minutes and stopped by washing the plate three times with 100 μl PBSplus 0.05% Tween. 40 μl of a one in 10000 dilution of 4G10-HRP antibody(Upstate Biotechnology, UBI 16-105. Upstate are part of MilliporeCorporation, 290 Concord Road, Billerca Mass. 01821 USA) made up in 0.5%(w/v) BSA/PBS was then added to each well and the plates incubated atroom temperature for one hour. Following this, the plates were thenwashed repeatedly with 100 μl PBS plus 0.05% Tween to remove all tracesof the antibody solution. 40 μl of 50 μg/ml3,3′,5,5′-Tetramethylbenzidine (Sigma, Catalogue No. T2885), 0.05Mphosphate-citrate buffer, containing 0.03% sodium perborate was added toeach well and the plates incubated at room temperature for twelveminutes. The colour reaction was stopped by the addition of 20 μl 2MH₂SO₄ and the plates read at 450 nm on a Spectrafluor Plus (TecanTrading AG, Switzerland). In the assay, compounds were tested at a rangeof concentrations. The mean data values for each concentration, alongwith untreated control wells and 100% inhibition control wells were usedto derive a plot of inhibition against concentration. From this data,the IC50 value or a percentage inhibition value at fixed concentrationmay be determined.

Percentage inhibition at 1 uM, as expressed herein, is a calculatedvalue based on the curve fit that was generated experimentally. From thefitted curve plot, the effect of compound at a concentration of 1 uM wascalculated as a percentage inhibition. The IC₅₀ value is theconcentration of test compound that inhibits 50% of FGFR kinaseactivity.

Results of FGFR Inhibition Tests for Examples

Example Activity class 1 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A 12 A 13B 14 B 15 A 16 B 17 B 18 B 19 A 20 A Activity: A less than 0.3 μM Bgreater than 0.3 μM and less than 1 μM C greater than 1 μM and less than30 μM Eg Example 14 is 732 nMCell AssaysCell pErk—Growth Factor Stimulated Erk Phosphorylation

These and other assays were used to evaluate the ability of a testcompound to inhibit growth factor stimulated cellular signalling inmammalian cell lines. This was achieved by measuring the amount ofreceptor tyrosine kinase regulated Erk phosphorylation within a cellfollowing compound treatment.

NIH 3T3 (ECACC, 93061524) cells were routinely passaged in DMEM (GibcoBRL, 41966) plus 10% foetal calf serum (FCS), 1% L-glutamine (Gibco BRL,25030) to a confluence not greater than 80%. To undertake the assay, NIH3T3's were seeded at 1×10⁴ cells/well in DMEM plus 10% foetal calfserum, 1% L-glutamine in 96 well plates (Costar, 3904) and incubated at37° C. (+5% CO₂) in a humidified incubator. Once the cells had fullyadhered (typically following 4-5 hours incubation) the media was removedfrom each well and the cells gently washed with 100 μl warm serum freemedia. 90 μl of serum free DMEM plus 1% L-glutamine was then added toeach well and the plates were returned to a humidified 37° C. (+5% CO₂)incubator. The following day, the plates were dosed with 10 μl compound(diluted from 10 mM stock in DMSO using serum free DMEM) and the plateswere returned to a humidified 37° C. (+5% CO₂) incubator for one hour.NIH 3T3 cells were then stimulated with a final concentration of 3 ng/mlbFGF (Sigma, F0291) for 20 minutes at 37° C. Following stimulation thecells were fixed by adding formaldehyde (4% v/v final concentration) andincubating at room temperature for 20 minutes. The fixative solution wasthen removed and the wells were washed twice with 100 μl phosphatebuffered saline (PBS/A) before permeabilising the cells by the additionof 50 μl/well 0.1% triton/PBS/A for 10 minutes at room temperature. Thepermeabilisation solution was then removed and the cells washed twicemore with 100 μl/well PBS/A before the addition of 50 μl/wellanti-phospho p44/42 antibody (Cell Signalling Technology, 9106), diluted1/500 with PBS/A plus 10% FCS. The anti-phospho p44/42 antibodyrecognises Erk phosphorylated at threonine 202 and tyrosine 204.Following incubation at room temperature for 2 hours, the antibodysolution was removed and the wells were washed twice with 100 μl/wellPBS/A. 50 μl/well 1/250 goat anti-mouse alexa fluor 488 secondaryantibody (Molecular Probes, A11001) and 1/10000 Hoescht (MolecularProbes, H-3570) diluted with PBS/A plus 10% FCS was added and the plateincubated in the dark at room temperature for one hour. Finally, theplates were washed three times with 100 μl/well PBS/A, leaving the finalwash in the wells before sealing the plates. The plates were read at 350nm and 488 nm using an Arrayscan (Cellomics). The mean average intensityfluorescence values for each test compound concentration, untreatedcontrol wells and 100% inhibition control wells were used to determinethe test compounds IC₅₀ value. IC₅₀ value is the concentration of testcompound that inhibits 50% of Erk phosphorylation.

Results of FGFR Inhibition Tests for Examples

Example Activity class 1 B 2 A 7 C 8 A 9 B 10 A 11 A 18 B Activity: Aless than 0.3 μM B greater than 0.3 μM and less than 1 μM C greater than1 μM and less than 30 μM Eg Example 18 is 877 nM.Cell FGFR1—Cell Based Inhibition of Transiently Expressed FGFR1 IIIcPhosphorylation (Measured Using Phospho-Specific Primary and FluorescentSecondary Antibodies).

This assay is designed to detect inhibitors of transiently expressedFGFR1 phosphorylation by antibody staining of fixed cells detected usingArrayScan technology. (For a description of Array Scan technology seehttp://www.cellomics.com/content/menu/Arrayscan/)

Cos-1 cells were routinely passaged in DMEM (Gibco BRL, 41966) plus 3%foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 25030) to aconfluence of 80%. To undertake the assay, Cos-1 cells were harvested at90-95% confluence for cell transfection. For each 96-well plate, 24 ulLipofectamine 2000 (Invitrogen, Catalogue No. 11668-019) was added to809 ul OptiMEM (Invitrogen, Catalogue No. 11058-021) and incubated atroom temperature for 5 minutes. For each 96 well plate, 20 ug 3′ FLAGtagged FGFR1/pcDNA3.1 (In-house clone 15, MSD 4793) was diluted withOptiMEM to a total volume of 833 ul. Equal volumes of DNA andLipofectamine 2000 were combined (DNA: Lipid=1:1.2 ratio) and incubatedat room temperature for 20 minutes. The “FLAG-tag” was apurification/detection tag which comprises the amino sequence:N-DYKDDDDK-C. The “FLAG-tag” was cloned at the N-terminus of FGFR1. Theclone was full-length, wild-type FGFR1 IIIc isoform.

The harvested Cos-1 cells are counted using a coulter counter anddiluted further with 1% FCS/DMEM to 2.5×10⁵ cells/ml. For each 96-well,8.33 ml cells were required. The complexed transfection solution wasadded to the cell solution and the cells were seeded at 2.5×10⁵cells/well in DMEM plus 1% foetal calf serum, 1% L-glutamine in 96 wellplates (Costar, 3904) and incubated at 37° C. (+5% CO₂) in a humidifiedincubator overnight (24 hrs). The following day, the plates were dosedwith 25 μl compound (diluted from 10 mM stock in DMSO using serum freeDMEM) and the plates were returned to a humidified 37° C. (+5% CO₂)incubator for one hour. Media was removed from the wells using vacuumaspiration; cells were fixed by adding 50 μl of 100% methanol to eachwell and incubated at room temperature for 20 minutes. The fixativesolution was then removed and the wells were washed once with 200 μlphosphate buffered saline (PBS/A) before permeabilising the cells by theaddition of 50 ul/well 0.1% triton/PBS/A for 20 minutes at roomtemperature. The permeabilisation solution was then removed and thecells washed once more with 200 ul/well PBS/A before the addition of 40μl 1/1000 primary antibody solution (Cell Signalling Technologies#CS3476; mouse anti-phospho FGFR1 diluted in PBS/A with 10% FCS+0.1%Tween20) to each well.

Following incubation at room temperature for 1 hour, the antibodysolution was removed and the wells were washed once with 200 ul/wellPBS/A. Then 40 μl 1/500 secondary antibody (A111005; goat anti-mouse594) solution and 1/10000 Hoechst (diluted together in PBS/A with 10%FCS+0.1% Tween 20) were added and the plate incubated in the dark atroom temperature for one hour. Finally, the plates were washed once with200 μl/well PBS/A, leaving the final wash in the wells before sealingthe plates. The plates were read on an Arrayscan (Cellomics). TheChannel 2 (594 nm) values obtained from undosed (max) and referencecompound (min) wells within a plate are used to set boundaries for 0%and 100% compound inhibition. Compound data was normalized against thesevalues to determine the dilution range of a test compound that gives 50%inhibition of phosphorylated FGFR1.

Cell FGFR1 (ECHO)—Cell Based Inhibition of Transiently Expressed FGFR1IIIc Phosphorylation Via Use of ECHO Technology (Measured UsingPhospho-Specific Primary and Fluorescent Secondary Antibodies).

This assay is designed to detect inhibitors of transiently expressedFGFR1 phosphorylation by antibody staining of fixed cells detected usingArrayScan technology.

Cos-1 cells were routinely passaged in DMEM (Gibco BRL, 41966) plus 3%foetal calf serum (FCS), 1% L-glutamine (Gibco BRL, 25030) to aconfluence of 80%. To undertake the assay, Cos-1 cells were harvested at90-95% confluence for cell transfection. For each 96-well plate, 24 μlLipofectamine 2000 was added to 809 ul OptiMEM and incubated at roomtemperature for 5 minutes. For each 96 well plate, 20 ug 3′ FLAG taggedFGFR1/pcDNA3.1 (In-house clone 15, MSD 4793) was diluted with OptiMEM toa total volume of 833 μl. Equal volumes of DNA and Lipofectamine 2000were combined (DNA: Lipid=1:1.2 ratio) and incubated at room temperaturefor 20 minutes.

The harvested Cos-1 cells are counted using a coulter counter anddiluted further with 1% FCS/DMEM to 2.5×10⁵ cells/ml. For each 96-well,8.33 ml cells were required. The complexed transfection solution wasadded to the cell solution and the cells were seeded at 2.5×10⁵cells/well in DMEM plus 1% foetal calf serum, 1% L-glutamine in 96 wellplates (Costar, 3904) and incubated at 37° C. (+5% CO₂) in a humidifiedincubator overnight (24 hrs).

The following day, compounds from dry weight samples were dissolved in100% DMSO to give 10 mM concentration. 40 μl of the compound wasdispensed into the wells of each quadrant across the 384 Labcyte plate(Labcyte Catalogue No. P-05525) (inclusive of a positive control (100%DMSO), a negative control (10 μM) and a reference compound (250 nM)).The 384 Labcyte plate was then transferred to the Hydra to dilute thecompounds 1:100 into the remaining wells of the quadrant. 70 μl of mediawas aspirated from the assay plate using the Quadra before the plate wastransferred onto the ECHO 550. The 384 Labcyte compound plate was alsotransferred onto the ECHO 550. Compound transfer to the assay plate onthe ECHO 550 was at concentration ranges 1) 10 μM, 2) 3 μM, 3) 1 μM, 4)0.3 μM, 5) 0.1 μM, 6) 0.01.

The plates were gently tapped to mix compound in with the cell media andleft to incubate at 37° C. with 5% CO₂ for 1 hour.

Media was removed from the wells using vacuum aspiration; cells werefixed by adding 50 μl of 100% methanol to each well and incubated atroom temperature for 20 minutes. The fixative solution was then removedand the wells were washed once with 200 μl phosphate buffered saline(PBS/A) before permeabilising the cells by the addition of 50 ul/well0.1% triton/PBS/A for 20 minutes at room temperature. Thepermeabilisation solution was then removed and the cells washed oncemore with 200 μl/well PBS/A before the addition of 40 μl 1/1000 primaryantibody solution (Cell Signalling Technologies #CS3476; mouseanti-phospho FGFR1 diluted in PBS/A with 10% FCS+0.1% Tween20) to eachwell.

Following incubation at room temperature for 1 hour, the antibodysolution was removed and the wells were washed once with 200 ul/wellPBS/A. Then 40 μl 1/500 secondary antibody (A11005; goat anti-mouse 594)solution and 1/10000 Hoechst (diluted together in PBS/A with 10%FCS+0.1% Tween 20) were added and the plate incubated in the dark atroom temperature for one hour. Finally, the plates were washed once with200 μl/well PBS/A, leaving the final wash in the wells before sealingthe plates. The plates were read on an Arrayscan (Cellomics). TheChannel 2 (594 nm) values obtained from undosed (max) and referencecompound (min) wells within a plate are used to set boundaries for 0%and 100% compound inhibition. Compound data was normalized against thesevalues to determine the dilution range of a test compound that gives 50%inhibition of phosphorylated FGFR1.

The invention claimed is:
 1. A method of treating cancer which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the cancer isselected from breast, multiple myeloma, bladder, endometrial, gastric,prostate, urothelial, squamous lung and ovarian cancers.
 2. A method oftreating cancer which comprises administering to a patient in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein the cancer isselected from breast, multiple myeloma, bladder, endometrial, gastric,prostate, urothelial, squamous lung and ovarian cancers.